Disease Information

General Information of the Disease (ID: DIS00028)

• Name: Bacterial infection
• ICD: ICD-11: 1A00-1C4Z

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 101 drug(s) in total

Acriflavine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein PmpM (PMPM) [1]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Acriflavine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32/pSTV28; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: PmpM is a multi drug efflux pump coupled with hydrogen ions, which reduces the intracellular drug concentration and produces drug resistance.

Amikacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [2]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Intergeneric lateral gene transfer
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa AR-2; 287
• Experiment for Molecule Alteration: PCR screening assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The 16S rRNA methylase gene has undergone intergeneric horizontal gene transfer from some aminoglycoside producing microorganisms to Pseudomonas aeruginosa, which is called rmtA. rmtA protect bacterial 16S rRNA from intrinsic aminoglycosides by methylation.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(6')-acetyltransferase type 1 (A6AC1) [3]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa Nk0001; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0002; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0003; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0004; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0005; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0006; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0007; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0008; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0009; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Micro-dilution method assay
• Mechanism Description: Recombinant AAC(6')-Iag protein showed aminoglycoside 6'-N-acetyltransferase activity using thin-layer chromatography (TLC) and MS spectrometric analysis. Escherichia coli carrying aac(6')-Iag showed resistance to amikacin, arbekacin, dibekacin, isepamicin, kanamycin, sisomicin, and tobramycin; but not to gentamicin.AAC(6')-Iag is a functional acetyltransferase that modifies alternate amino groups on the AGs.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [4]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• Experiment for Molecule Alteration: PCR mapping and sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Aac(3)-Ic gene could contribute to aminoglycoside resistance with a pattern typical of AAC(3)-I enzymes.

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [6]

• Resistant Disease: Streptococcus faecalis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Amikacin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain JM 10; 562
• In Vitro Model: Escherichia coli strain k802; 562
• In Vitro Model: Streptococcus faecnlis strain JHZ-15; 1351
• Experiment for Molecule Alteration: Chemical sequencing method assay
• Experiment for Drug Resistance: Disc sensitivity tests assay
• Mechanism Description: Strain BM2182 was examined for aminoglyco- side-modifying activities. That kanamycin B was modified and tobramycin (3'-deoxykanamycin B) was not, indicates that the 3'-hydroxyl group is the site of phosphorylation. That butirosin, lividomycin A, and amikacin were phosphorylated indicates that the enzyme is APH-III.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [7]

• Resistant Disease: Serratia marcescens infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Key Molecule: Aminoglycoside N(3)-acetyltransferase III (A3AC3) [8], [9]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Serratia marcescens strain 82041944; 615
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The AAC(3)-V resistance mechanism is characterized by high-level resistance to the aminoglycosides gentamicin, netilmicin, 2'-N-ethylnetilmicin, and 6'-N-ethylnetilmicin and moderate resistance levels to tobramycin.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: TolC family outer membrane protein (TOLC) [10]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AYE WT; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO Omega abuO; 509173
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: AbuO, an OMP, confers broad-spectrum antimicrobial resistance via active efflux in A. baumannii.

Amoxicillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Acinetobacter baumannii CIP70.10; 470
• In Vitro Model: Klebsiella pneumoniae kP3; 1290996
• In Vitro Model: Pseudomonas aeruginosa PU21; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: K. pneumoniae kP3 was resistant to all Beta-lactams, including carbapenems, and expressed the carbapenem-hydrolyzing Beta-lactamase OXA-181, which differs from OXA-48 by four amino acid substitutions. Compared to OXA-48, OXA-181 possessed a very similar hydrolytic profile.

Key Molecule: Beta-lactamase (BLA) [12], [13]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis H37Rv; 83332
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Mycobacterium smegmatis PM274; 1772
• In Vitro Model: Mycobacterium smegmatis PM759; 1772
• In Vitro Model: Mycobacterium smegmatis PM791; 1772
• In Vitro Model: Mycobacterium smegmatis PM876; 1772
• In Vitro Model: Mycobacterium smegmatis PM939; 1772
• In Vitro Model: Mycobacterium smegmatis PM976; 1772
• In Vitro Model: Mycobacterium tuberculosis PM638; 1773
• In Vitro Model: Mycobacterium tuberculosis PM669; 1773
• In Vitro Model: Mycobacterium tuberculosis PM670; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: Mycobacteria produce Beta-lactamases and are intrinsically resistant to Beta-lactam antibiotics.The mutants M. tuberculosis PM638 (detablaC1) and M. smegmatis PM759 (detablaS1) showed an increase in susceptibility to Beta-lactam antibiotics.

Key Molecule: Beta-lactamase (BLA) [14], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli JM101; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Beta-lactamases (Beta-lactamhydrolase, EC 3.5.2.6), responsible for most of the resistance to Beta-lactam antibiotics, are often plasmid mediated.The OXA-1 beta-lactamase gene is part of Tn2603, which is borne on the R plasmid RGN238.

Key Molecule: Beta-lactamase (BLA) [15], [16]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli Gre-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The first extended-spectrum Beta-lactamase (ESBL) of the CTX-M type (MEN-1/CTX-M-1) was reported at the beginning of the 1990s.CTX-M-27 differed from CTX-M-14 only by the substitution D240G and was the third CTX-M enzyme harbouring this mutation after CTX-M-15 and CTX-M-16. The Gly-240-harbouring enzyme CTX-M-27 conferred to Escherichia coli higher MICs of ceftazidime (MIC, 8 versus 1 mg/L) than did the Asp-240-harbouring CTX-M-14 enzyme.

Key Molecule: Beta-lactamase (BLA) [15], [17], [18]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Citrobacter freundii 2526/96; 546
• In Vitro Model: Escherichia coli isolates; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: We have reported recently the DNA sequence of another Beta-lactamase, CTX- M-15, from Indian enterobacterial isolates that were resistant to both cefotaxime and ceftazidime.CTX-M-15 has a single amino acid change [Asp-240-Gly (Ambler numbering)]7 compared with CTX-M-3.

Ampicillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [12], [13]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis H37Rv; 83332
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Mycobacterium smegmatis PM274; 1772
• In Vitro Model: Mycobacterium smegmatis PM759; 1772
• In Vitro Model: Mycobacterium smegmatis PM791; 1772
• In Vitro Model: Mycobacterium smegmatis PM876; 1772
• In Vitro Model: Mycobacterium smegmatis PM939; 1772
• In Vitro Model: Mycobacterium smegmatis PM976; 1772
• In Vitro Model: Mycobacterium tuberculosis PM638; 1773
• In Vitro Model: Mycobacterium tuberculosis PM669; 1773
• In Vitro Model: Mycobacterium tuberculosis PM670; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: Mycobacteria produce Beta-lactamases and are intrinsically resistant to Beta-lactam antibiotics.The mutants M. tuberculosis PM638 (detablaC1) and M. smegmatis PM759 (detablaS1) showed an increase in susceptibility to Beta-lactam antibiotics.

Key Molecule: Beta-lactamase (BLA) [14], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli JM101; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Beta-lactamases (Beta-lactamhydrolase, EC 3.5.2.6), responsible for most of the resistance to Beta-lactam antibiotics, are often plasmid mediated.The OXA-1 beta-lactamase gene is part of Tn2603, which is borne on the R plasmid RGN238.

Key Molecule: Beta-lactamase (BLA) [15], [19], [20]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.L76N+p.V84I+p.A184V
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• Mechanism Description: The TEM Beta-lactamases are among the best-studied antibiotic resistance enzymes around.TEM-1, the first TEM allele identified, was isolated from penicillin-resistant bacteria in 1963.

Key Molecule: Beta-lactamase (BLA) [15], [19], [20]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.L76N
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• Mechanism Description: The TEM Beta-lactamases are among the best-studied antibiotic resistance enzymes around.TEM-1, the first TEM allele identified, was isolated from penicillin-resistant bacteria in 1963.

Key Molecule: Beta-lactamase (BLA) [21]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• Experiment for Molecule Alteration: DNA sequencing and protein assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: P. aeruginosa harbors two naturally encoded Beta-lactamase genes, one of which encodes an inducible cephalosporinase and the other of which encodes a constitutively expressed oxacillinase. OXA-50 is a kind of oxacillinase which lead to drug resistance.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [22]

• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Key Molecule: Metallo-beta-lactamase (VIM1) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: A. xylosoxydans AX22 exhibited broad-spectrum resistance to Beta-lactams and aminoglycosides. The Beta-lactam resistance pattern (including piperacillin, ceftazidime, and carbapenem resistance) was unusual for this species, and the high-level carbapenem resistance suggested the production of an acquired carbapenemase. In fact, carbapenemase activity was detected in a crude extract of AX22 (specific activity, 184 +/- 12 U/mg of protein), and this activity was reduced (>80%) after incubation of the crude extract with 2 mM EDTA, suggesting the presence of a metallo-Beta-lactamase determinant.

Key Molecule: Beta-lactamase (BLA) [15], [23]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V77A+p.D114N+p.S140A+p.N288D
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Citrobacter freundii strain 2524/96; 546
• In Vitro Model: Citrobacter freundii strain 2525/96; 546
• In Vitro Model: Citrobacter freundii strain 2526/96; 546
• In Vitro Model: Escherichia coli strain 2527/96; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Sequencing has revealed that C. freundii isolates produced a new CTX-M-3 enzyme which is very closely related to the CTX-M-1/MEN-1 Beta-lactamase.

Key Molecule: Imipenem-hydrolyzing beta-lactamase (NMCA) [24]

• Resistant Disease: Enterobacter cloacae infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain JM109; 83333
• In Vitro Model: Enterobacter cloacae strain NOR-1; 550
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Here we report a gene encoding a carbapenemase, which was cloned from the chromosome of a clinical isolate of Enterobacter cloacae, strain NOR-1, into pACYC184 plasmid in Escherichia coli. Unlike all the sequenced carbapenemases, which are class B metallo-beta-lactamases, the mature protein (NmcA) is a class A serine beta-lactamase. NmcA shares the highest amino acid identity (50%) with the extended-spectrum class A beta-lactamase MEN-1 from Escherichia coli.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter ATPase subunit (ABCS) [25], [26], [27]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis isolates; 1351
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Multidrug efflux pump extraction, purification, and sequencing showed the distribution of mefA and msrA/msrB efflux pumps.

Key Molecule: Putative ABC transporter ATP-binding component (OTRC) [28]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli ET12567 (pUZ8002); 562
• In Vitro Model: Streptomyces rimosus M4018; 1927
• In Vitro Model: Streptomyces rimosus SR16; 1927
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: OtrC is a multidrug resistance protein based on an ATP hydrolysis-dependent active efflux mechanism.OtrC is a multidrug resistance protein based on an ATP hydrolysis-dependent active efflux mechanism.

Arbekacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [2]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Intergeneric lateral gene transfer
• Resistant Drug: Arbekacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa AR-2; 287
• Experiment for Molecule Alteration: PCR screening assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The 16S rRNA methylase gene has undergone intergeneric horizontal gene transfer from some aminoglycoside producing microorganisms to Pseudomonas aeruginosa, which is called rmtA. rmtA protect bacterial 16S rRNA from intrinsic aminoglycosides by methylation.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(6')-acetyltransferase type 1 (A6AC1) [3]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Arbekacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa Nk0001; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0002; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0003; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0004; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0005; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0006; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0007; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0008; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0009; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Micro-dilution method assay
• Mechanism Description: Recombinant AAC(6')-Iag protein showed aminoglycoside 6'-N-acetyltransferase activity using thin-layer chromatography (TLC) and MS spectrometric analysis. Escherichia coli carrying aac(6')-Iag showed resistance to amikacin, arbekacin, dibekacin, isepamicin, kanamycin, sisomicin, and tobramycin; but not to gentamicin.AAC(6')-Iag is a functional acetyltransferase that modifies alternate amino groups on the AGs.

Aztreonam

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [15], [29]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Aztreonam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Klebsiella pneumoniae strain HEL-1; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The phenotype of Klebsiella pneumoniae HEL-1 indicates a plasmidic cephamycinase gene (blaCMY-2),which is responsible for cephamycin resistance.

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• Resistant Drug: Aztreonam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Acinetobacter baumannii CIP70.10; 470
• In Vitro Model: Klebsiella pneumoniae kP3; 1290996
• In Vitro Model: Pseudomonas aeruginosa PU21; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: K. pneumoniae kP3 was resistant to all Beta-lactams, including carbapenems, and expressed the carbapenem-hydrolyzing Beta-lactamase OXA-181, which differs from OXA-48 by four amino acid substitutions. Compared to OXA-48, OXA-181 possessed a very similar hydrolytic profile.

Key Molecule: Metallo-beta-lactamase (VIM1) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Aztreonam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: A. xylosoxydans AX22 exhibited broad-spectrum resistance to Beta-lactams and aminoglycosides. The Beta-lactam resistance pattern (including piperacillin, ceftazidime, and carbapenem resistance) was unusual for this species, and the high-level carbapenem resistance suggested the production of an acquired carbapenemase. In fact, carbapenemase activity was detected in a crude extract of AX22 (specific activity, 184 +/- 12 U/mg of protein), and this activity was reduced (>80%) after incubation of the crude extract with 2 mM EDTA, suggesting the presence of a metallo-Beta-lactamase determinant.

Key Molecule: Beta-lactamase (BLA) [15], [23]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V77A+p.D114N+p.S140A+p.N288D
• Resistant Drug: Aztreonam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Citrobacter freundii strain 2524/96; 546
• In Vitro Model: Citrobacter freundii strain 2525/96; 546
• In Vitro Model: Citrobacter freundii strain 2526/96; 546
• In Vitro Model: Escherichia coli strain 2527/96; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Sequencing has revealed that C. freundii isolates produced a new CTX-M-3 enzyme which is very closely related to the CTX-M-1/MEN-1 Beta-lactamase.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Pyruvate decarboxylase 5 (PDC5) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• Resistant Drug: Aztreonam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Key Molecule: Pyruvate decarboxylase 3 (PDC3) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T97A
• Resistant Drug: Aztreonam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Bacitracin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Undecaprenyl-diphosphatase (UPPP) [31]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Bacitracin A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Enterococcus faecalis V583; 226185
• In Vitro Model: Escherichia coli MC1061; 1211845
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Binding of bacitracin to UPP prevents its dephosphorylation, thereby disrupting the regeneration of UP.Depletion of the available carrier lipids leads to the inhibition of the cell wall synthesis, resulting eventually in cell death.Low-level bacitracin resistance in E. faecalis is mediated by a BacA-type UppP.

Bacitracin F

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Undecaprenyl-diphosphatase (UPPP) [31]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Bacitracin F
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Enterococcus faecalis V583; 226185
• In Vitro Model: Escherichia coli MC1061; 1211845
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Binding of bacitracin to UPP prevents its dephosphorylation, thereby disrupting the regeneration of UP.Depletion of the available carrier lipids leads to the inhibition of the cell wall synthesis, resulting eventually in cell death.Low-level bacitracin resistance in E. faecalis is mediated by a BacA-type UppP.

Bacitracin methylene disalicylate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Undecaprenyl-diphosphatase (UPPP) [31]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Bacitracin methylene disalicylate
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Enterococcus faecalis V583; 226185
• In Vitro Model: Escherichia coli MC1061; 1211845
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Binding of bacitracin to UPP prevents its dephosphorylation, thereby disrupting the regeneration of UP.Depletion of the available carrier lipids leads to the inhibition of the cell wall synthesis, resulting eventually in cell death.Low-level bacitracin resistance in E. faecalis is mediated by a BacA-type UppP.

Balofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: (Na+)-NQR maturation NqrM (nqrM) [32]

• Resistant Disease: Vibrio alginolyticus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Balofloxacin
• Experimental Note: Discovered Using In-vivo Testing Model
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: Na(+)-NQR is a membrane-embedded NADH dehydrogenase. Down-regulation of the Na(+)-NQR is required for V. alginolyticus in resistance to BLFX. It is known that the resistant mechanisms of a quinolone antibiotic are through the inhibition of DNA-gyrase which is required for DNA synthesis, and expressional changes of OM proteins which elevate pump activity and decrease OM permeability.

Benzalkonium chloride

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Protein QacZ (QACZ) [33]

• Resistant Disease: Enterococcal infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Benzalkonium chloride
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Enterococcus faecalis EF-SAVE1; 1244142
• In Vitro Model: Enterococcus faecalis V583ErmS; 1244142
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MIC determination assay
• Mechanism Description: A derivative strain of V583, susceptible to erythromycin (V583ErmS), was complemented with pORI23 carrying the qacZ gene (strain EF-SAVE1). MICs of benzalkonium chloride, chlorhexidine and ethidium bromide were determined for the complemented strain and wild-type. The complemented strain, EF-SAVE1, presented a higher MIC of benzalkonium chloride (8 mg/L) than V583ErmS (4 mg/L); the MICs of chlorhexidine and ethidium bromide were the same for both strains, 4 mg/L and 16 mg/L, respectively. Expression of qacZ was found to be higher in EF-SAVE1 and constitutive, i.e. not inducible by any of the three tested bi.

Key Molecule: Multidrug resistance protein PmpM (PMPM) [1]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Benzalkonium chloride
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32/pSTV28; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: PmpM is a multi drug efflux pump coupled with hydrogen ions, which reduces the intracellular drug concentration and produces drug resistance.

Benzylpenicillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [34]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Benzylpenicillin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM 160(Y); 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM158; 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM159; 1063
• Experiment for Molecule Alteration: Sodium dodecyl sulfate-PAGE assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Thirteen strains of the gram-negative, facultative phototrophic bacterium Rhodobacter sphaeroides were examined fro susceptibility to beta-lactam antibiotics. All strains were sensitive to the semisynthetic penicillins ampicillin, carbenicillin, oxacillin, cloxacillin, and methicillin, but 10 of the 13 strains were resistant to penicillin G, as well as a number of cephalosporins, such as cephalothin, cephapirin, and cephalosporin C. A beta-lactamase (EC 3.5.2.6) with strong cephalosporinase activity was detected in all of the resistant strains of R. sphaeroides. With strain Y-1 as a model, it was shown that the beta-lactamase was inducible by penicillin G, cephalosporin C, cephalothin, and to some minor extent, cephapirin.

Capreomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Capreomycin acetyltransferase (CPAA) [35]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Capreomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Paenibacillus sp. LC231; 1120679
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: CpaA inactivates capreomycin by acetylating the alpha-amino group of diaminopropionic acid at position 1.

Carbenicillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [12], [13]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carbenicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis H37Rv; 83332
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Mycobacterium smegmatis PM274; 1772
• In Vitro Model: Mycobacterium smegmatis PM759; 1772
• In Vitro Model: Mycobacterium smegmatis PM791; 1772
• In Vitro Model: Mycobacterium smegmatis PM876; 1772
• In Vitro Model: Mycobacterium smegmatis PM939; 1772
• In Vitro Model: Mycobacterium smegmatis PM976; 1772
• In Vitro Model: Mycobacterium tuberculosis PM638; 1773
• In Vitro Model: Mycobacterium tuberculosis PM669; 1773
• In Vitro Model: Mycobacterium tuberculosis PM670; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: Mycobacteria produce Beta-lactamases and are intrinsically resistant to Beta-lactam antibiotics.The mutants M. tuberculosis PM638 (detablaC1) and M. smegmatis PM759 (detablaS1) showed an increase in susceptibility to Beta-lactam antibiotics.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: TolC family outer membrane protein (TOLC) [10]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carbenicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AYE WT; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO Omega abuO; 509173
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: AbuO, an OMP, confers broad-spectrum antimicrobial resistance via active efflux in A. baumannii.

Cefadroxil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Antigen peptide transporter 1 (TAP1) [36]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cefadroxil
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Ussing chamber system assay
• Mechanism Description: Cefadroxil and methotrexate (each 10 uM) were selected as substrates to evaluate the functions of the uptake transport mediated by PEPT1 and PCFT, respectively. Gly-Sar (20 mM) and folate (200 uM), typical substrates of PEPT1 and PCFT, respectively, were used to saturate the functions of PEPT1 and PCFT. The mucosal-to-serosal transport and mucosal uptake of cefadroxil and methotrexate were significantly decreased in the presence of PEPT1/PCFT inhibitor cocktail in all batches of tissue sections.

Cefalotin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• Resistant Drug: Cefalotin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Acinetobacter baumannii CIP70.10; 470
• In Vitro Model: Klebsiella pneumoniae kP3; 1290996
• In Vitro Model: Pseudomonas aeruginosa PU21; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: K. pneumoniae kP3 was resistant to all Beta-lactams, including carbapenems, and expressed the carbapenem-hydrolyzing Beta-lactamase OXA-181, which differs from OXA-48 by four amino acid substitutions. Compared to OXA-48, OXA-181 possessed a very similar hydrolytic profile.

Key Molecule: Beta-lactamase (BLA) [14], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cefalotin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli JM101; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Beta-lactamases (Beta-lactamhydrolase, EC 3.5.2.6), responsible for most of the resistance to Beta-lactam antibiotics, are often plasmid mediated.The OXA-1 beta-lactamase gene is part of Tn2603, which is borne on the R plasmid RGN238.

Key Molecule: Beta-lactamase (BLA) [21]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cefalotin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• Experiment for Molecule Alteration: DNA sequencing and protein assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: P. aeruginosa harbors two naturally encoded Beta-lactamase genes, one of which encodes an inducible cephalosporinase and the other of which encodes a constitutively expressed oxacillinase. AmpC is a kind of cephalosporinase which lead to drug resistance.

Key Molecule: Beta-lactamase (BLA) [16], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Cefalotin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli Gre-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The first extended-spectrum Beta-lactamase (ESBL) of the CTX-M type (MEN-1/CTX-M-1) was reported at the beginning of the 1990s.CTX-M-27 differed from CTX-M-14 only by the substitution D240G and was the third CTX-M enzyme harbouring this mutation after CTX-M-15 and CTX-M-16. The Gly-240-harbouring enzyme CTX-M-27 conferred to Escherichia coli higher MICs of ceftazidime (MIC, 8 versus 1 mg/L) than did the Asp-240-harbouring CTX-M-14 enzyme.

Key Molecule: Beta-lactamase (BLA) [15], [17], [18]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Cefalotin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Citrobacter freundii 2526/96; 546
• In Vitro Model: Escherichia coli isolates; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: We have reported recently the DNA sequence of another Beta-lactamase, CTX- M-15, from Indian enterobacterial isolates that were resistant to both cefotaxime and ceftazidime.CTX-M-15 has a single amino acid change [Asp-240-Gly (Ambler numbering)]7 compared with CTX-M-3.

Key Molecule: Beta-lactamase (BLA) [34]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cefalotin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM 160(Y); 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM158; 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM159; 1063
• Experiment for Molecule Alteration: Sodium dodecyl sulfate-PAGE assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Thirteen strains of the gram-negative, facultative phototrophic bacterium Rhodobacter sphaeroides were examined fro susceptibility to beta-lactam antibiotics. All strains were sensitive to the semisynthetic penicillins ampicillin, carbenicillin, oxacillin, cloxacillin, and methicillin, but 10 of the 13 strains were resistant to penicillin G, as well as a number of cephalosporins, such as cephalothin, cephapirin, and cephalosporin C. A beta-lactamase (EC 3.5.2.6) with strong cephalosporinase activity was detected in all of the resistant strains of R. sphaeroides. With strain Y-1 as a model, it was shown that the beta-lactamase was inducible by penicillin G, cephalosporin C, cephalothin, and to some minor extent, cephapirin.

Cefametazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [15], [29]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cefametazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Klebsiella pneumoniae strain HEL-1; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The phenotype of Klebsiella pneumoniae HEL-1 indicates a plasmidic cephamycinase gene (blaCMY-2),which is responsible for cephamycin resistance.

Cefazolin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Outer membrane porin C (OMPC) [37], [38], [39]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cefazolin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli 1422; 562
• In Vitro Model: Escherichia coli 1437; 562
• In Vitro Model: Escherichia coli B1343; 562
• In Vitro Model: Escherichia coli B1350; 562
• In Vitro Model: Escherichia coli B1421; 562
• In Vitro Model: Escherichia coli pop1010; 562
• Experiment for Drug Resistance: Disk diffusion test assay
• Mechanism Description: Permeability of the outer membrane to lowmolecular-weight hydrophilic molecules is due to the presence of porin protein molecules such as OmpF and OmpC, which form pores in the outer membrane that allow small molecules to diffuse rapidly into the periplasmic space.The case of cephaloridine and cefazolin is remarkable because mutants lacking the OmpF or the OmpC proteins individually were as susceptible to cefaloridine and cefazolin as was the wild type, but mutants lacking both proteins were resistant to these Beta-lactams.

Cefepime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [40]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cefepime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Pseudomonas aeruginosa PU21; 287
• In Vitro Model: Escherichia coli strain k-12 C600; 83333
• In Vitro Model: Pseudomonas aeruginosa 104116; 287
• In Vitro Model: Pseudomonas aeruginosa SOF-1; 287
• Experiment for Molecule Alteration: Southern technique assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: Pseudomonas aeruginosa clinical isolate SOF-1 was resistant to cefepime and susceptible to ceftazidime. This resistance phenotype was explained by the expression of OXA-31, which shared 98% amino acid identity with a class D beta-lactamase, OXA-1. The oxa-31 gene was located on a ca. 300-kb nonconjugative plasmid and on a class 1 integron. No additional efflux mechanism for cefepime was detected in P. aeruginosa SOF-1. Resistance to cefepime and susceptibility to ceftazidime in P. aeruginosa were conferred by OXA-1 as well.

Key Molecule: Metallo-beta-lactamase (VIM1) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cefepime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: A. xylosoxydans AX22 exhibited broad-spectrum resistance to Beta-lactams and aminoglycosides. The Beta-lactam resistance pattern (including piperacillin, ceftazidime, and carbapenem resistance) was unusual for this species, and the high-level carbapenem resistance suggested the production of an acquired carbapenemase. In fact, carbapenemase activity was detected in a crude extract of AX22 (specific activity, 184 +/- 12 U/mg of protein), and this activity was reduced (>80%) after incubation of the crude extract with 2 mM EDTA, suggesting the presence of a metallo-Beta-lactamase determinant.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Pyruvate decarboxylase 5 (PDC5) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• Resistant Drug: Cefepime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Key Molecule: Pyruvate decarboxylase 3 (PDC3) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T97A
• Resistant Drug: Cefepime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Cefmetazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Beta-lactam-inducible penicillin-binding protein (MECA) [41]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cefmetazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain TG1; 562
• In Vitro Model: Staphylococcus aureus strain SA113; 1280
• In Vitro Model: Staphylococcus aureus strain kU201; 1280
• In Vitro Model: Staphylococcus aureus strain kU201E; 1280
• In Vitro Model: Staphylococcus aureus strain kU203; 1280
• In Vitro Model: Staphylococcus aureus strain Tk388E; 1280
• In Vitro Model: Staphylococcus aureus strain Tk784; 1280
• Experiment for Molecule Alteration: Genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Expression and inducibility in staphylococcus aureus of the mecA Gene, which encodes a methicillin-resistant S. aureus-specific penicillin-binding protein.

Cefotaxime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• Resistant Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Acinetobacter baumannii CIP70.10; 470
• In Vitro Model: Klebsiella pneumoniae kP3; 1290996
• In Vitro Model: Pseudomonas aeruginosa PU21; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: K. pneumoniae kP3 was resistant to all Beta-lactams, including carbapenems, and expressed the carbapenem-hydrolyzing Beta-lactamase OXA-181, which differs from OXA-48 by four amino acid substitutions. Compared to OXA-48, OXA-181 possessed a very similar hydrolytic profile.

Key Molecule: Beta-lactamase (BLA) [42]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Y221H
• Resistant Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli EC13; 562
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: Disk diffusion test assay
• Mechanism Description: The CMY-136 Beta-lactamase, a Y221H point mutant derivative of CMY-2,confers an increased level of resistance to ticarcillin, cefuroxime, cefotaxime, and ceftolozane/tazobactam.

Key Molecule: Beta-lactamase (BLA) [43]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Mutantion; p.V231S
• Resistant Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli VA1171/10; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Quadruple disc test assay
• Mechanism Description: Molecular methods revealed a novel, plasmid-localized variant of CMY-2 with a substitution of valine 231 for serine (V231S), which was designated CMY-42. Like the CMY-2-like AmpC beta-lactamase CMY-30, carrying the substitution V231G, CMY-42 displayed increased activity toward expanded spectrum cephalosporins.

Key Molecule: Beta-lactamase (BLA) [15], [19], [20]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V84I+p.A184V
• Resistant Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• Mechanism Description: The TEM Beta-lactamases are among the best-studied antibiotic resistance enzymes around.TEM-1, the first TEM allele identified, was isolated from penicillin-resistant bacteria in 1963.

Key Molecule: Beta-lactamase (BLA) [15], [17], [18]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Citrobacter freundii 2526/96; 546
• In Vitro Model: Escherichia coli isolates; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: We have reported recently the DNA sequence of another Beta-lactamase, CTX- M-15, from Indian enterobacterial isolates that were resistant to both cefotaxime and ceftazidime.CTX-M-15 has a single amino acid change [Asp-240-Gly (Ambler numbering)]7 compared with CTX-M-3.

Key Molecule: Metallo-beta-lactamase (VIM1) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: A. xylosoxydans AX22 exhibited broad-spectrum resistance to Beta-lactams and aminoglycosides. The Beta-lactam resistance pattern (including piperacillin, ceftazidime, and carbapenem resistance) was unusual for this species, and the high-level carbapenem resistance suggested the production of an acquired carbapenemase. In fact, carbapenemase activity was detected in a crude extract of AX22 (specific activity, 184 +/- 12 U/mg of protein), and this activity was reduced (>80%) after incubation of the crude extract with 2 mM EDTA, suggesting the presence of a metallo-Beta-lactamase determinant.

Key Molecule: Beta-lactamase (BLA) [15], [23]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V77A+p.D114N+p.S140A+p.N288D
• Resistant Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Citrobacter freundii strain 2524/96; 546
• In Vitro Model: Citrobacter freundii strain 2525/96; 546
• In Vitro Model: Citrobacter freundii strain 2526/96; 546
• In Vitro Model: Escherichia coli strain 2527/96; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Sequencing has revealed that C. freundii isolates produced a new CTX-M-3 enzyme which is very closely related to the CTX-M-1/MEN-1 Beta-lactamase.

Cefotetan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [15], [29]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cefotetan
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Klebsiella pneumoniae strain HEL-1; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The phenotype of Klebsiella pneumoniae HEL-1 indicates a plasmidic cephamycinase gene (blaCMY-2),which is responsible for cephamycin resistance.

Cefoxitin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [15], [29]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cefoxitin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Klebsiella pneumoniae strain HEL-1; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The phenotype of Klebsiella pneumoniae HEL-1 indicates a plasmidic cephamycinase gene (blaCMY-2),which is responsible for cephamycin resistance.

Key Molecule: Beta-lactamase (BLA) [44]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V88L+p.M154L
• Resistant Drug: Cefoxitin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli ST648; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: NDM-5 differed from existing enzymes due to substitutions at positions 88 (Val - Leu) and 154 (Met - Leu) and reduced the susceptibility of Escherichia coli TOP10 transformants to expanded-spectrum cephalosporins and carbapenems when expressed under its native promoter.

Key Molecule: Penicillin binding protein PBP 2 (PBP2) [45]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cefoxitin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• In Vitro Model: Staphylococcus aureus M10/0061; 1280
• In Vitro Model: Staphylococcus aureus M10/0148; 1280
• In Vitro Model: Staphylococcus aureus WGB8404; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Disk diffusion test assay; Etest assay
• Mechanism Description: Methicillin resistance in staphylococci is mediated by penicillin binding protein 2a (PBP 2a), encoded by mecA on mobile staphylococcal cassette chromosome mec (SCCmec) elements.Whole-genome sequencing of one isolate (M10/0061) revealed a 30-kb SCCmec element encoding a class E mec complex with highly divergent blaZ-mecA-mecR1-mecI, a type 8 cassette chromosome recombinase (ccr) complex consisting of ccrA1-ccrB3, an arsenic resistance operon, and flanking direct repeats (DRs).

Key Molecule: Beta-lactamase (BLA) [43]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Mutantion; p.V231S
• Resistant Drug: Cefoxitin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli VA1171/10; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Quadruple disc test assay
• Mechanism Description: Molecular methods revealed a novel, plasmid-localized variant of CMY-2 with a substitution of valine 231 for serine (V231S), which was designated CMY-42. Like the CMY-2-like AmpC beta-lactamase CMY-30, carrying the substitution V231G, CMY-42 displayed increased activity toward expanded spectrum cephalosporins.

Key Molecule: Beta-lactamase (BLA) [15], [23]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V77A+p.D114N+p.S140A+p.N288D
• Resistant Drug: Cefoxitin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Citrobacter freundii strain 2524/96; 546
• In Vitro Model: Citrobacter freundii strain 2525/96; 546
• In Vitro Model: Citrobacter freundii strain 2526/96; 546
• In Vitro Model: Escherichia coli strain 2527/96; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Sequencing has revealed that C. freundii isolates produced a new CTX-M-3 enzyme which is very closely related to the CTX-M-1/MEN-1 Beta-lactamase.

Cefpirome

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [15], [17], [18]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Cefpirome
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Citrobacter freundii 2526/96; 546
• In Vitro Model: Escherichia coli isolates; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: We have reported recently the DNA sequence of another Beta-lactamase, CTX- M-15, from Indian enterobacterial isolates that were resistant to both cefotaxime and ceftazidime.CTX-M-15 has a single amino acid change [Asp-240-Gly (Ambler numbering)]7 compared with CTX-M-3.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Pyruvate decarboxylase 5 (PDC5) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• Resistant Drug: Cefpirome
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Key Molecule: Pyruvate decarboxylase 3 (PDC3) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T97A
• Resistant Drug: Cefpirome
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Cefradine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [34]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cefradine
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM 160(Y); 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM158; 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM159; 1063
• Experiment for Molecule Alteration: Sodium dodecyl sulfate-PAGE assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Thirteen strains of the gram-negative, facultative phototrophic bacterium Rhodobacter sphaeroides were examined fro susceptibility to beta-lactam antibiotics. All strains were sensitive to the semisynthetic penicillins ampicillin, carbenicillin, oxacillin, cloxacillin, and methicillin, but 10 of the 13 strains were resistant to penicillin G, as well as a number of cephalosporins, such as cephalothin, cephapirin, and cephalosporin C. A beta-lactamase (EC 3.5.2.6) with strong cephalosporinase activity was detected in all of the resistant strains of R. sphaeroides. With strain Y-1 as a model, it was shown that the beta-lactamase was inducible by penicillin G, cephalosporin C, cephalothin, and to some minor extent, cephapirin.

Ceftazidime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [15], [29]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Klebsiella pneumoniae strain HEL-1; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The phenotype of Klebsiella pneumoniae HEL-1 indicates a plasmidic cephamycinase gene (blaCMY-2),which is responsible for cephamycin resistance.

Key Molecule: TMB-2 metallo-beta-lactamase (BTMB2) [46]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter genomospecies 14BJ MRY12-226; 48296
• In Vitro Model: Acinetobacter pittii. MRY12-142; 1255681
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: Tripoli metallo-Beta-lactamase 2 (TMB-2), a variant of blaTMB-1 can inactivate the Beta-lactams.

Key Molecule: Metallo beta lactamase (TMB1) [47]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Achromobacter xylosoxidans AES301; 85698
• In Vitro Model: Escherichia coli J53; 1144303
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: These enzymes very efficiently hydrolyze all Beta-lactams, including carbapenems (with the exception of aztreonam), and the Beta-lactamase genes most often are located on transferable genetic platforms, namely, either ISCR elements or class 1 integrons sometimes embedded in Tn21- or Tn402-like transposons.A novel MBL, TMB-1 (for Tripoli metallo-Beta-lactamase) can inactivate the antibiotics.

Key Molecule: Beta-lactamase (BLA) [44]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V88L+p.M154L
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli ST648; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: NDM-5 differed from existing enzymes due to substitutions at positions 88 (Val - Leu) and 154 (Met - Leu) and reduced the susceptibility of Escherichia coli TOP10 transformants to expanded-spectrum cephalosporins and carbapenems when expressed under its native promoter.

Key Molecule: Beta-lactamase (BLA) [43]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V231S
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli VA1171/10; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Quadruple disc test assay
• Mechanism Description: Molecular methods revealed a novel, plasmid-localized variant of CMY-2 with a substitution of valine 231 for serine (V231S), which was designated CMY-42. Like the CMY-2-like AmpC beta-lactamase CMY-30, carrying the substitution V231G, CMY-42 displayed increased activity toward expanded spectrum cephalosporins.

Key Molecule: CATB10-Ib variant (CATB10) [48]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa TS-103; 287
• In Vitro Model: Pseudomonas aeruginosa TS-832035; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: P. aeruginosa TS-832035 produces a carbapenemase, coded by a blaVIM-1 determinant carried by the chromosomal class 1 integron In70.2 (containing also the aacA4, aphA15, and aadA1 genes in its cassette array),which induce the resistance to carbapenems.

Key Molecule: Beta-lactamase (BLA) [15], [19], [20]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V84I+p.A184V
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• Mechanism Description: The TEM Beta-lactamases are among the best-studied antibiotic resistance enzymes around.TEM-1, the first TEM allele identified, was isolated from penicillin-resistant bacteria in 1963.

Key Molecule: Beta-lactamase (BLA) [15], [17], [18]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Citrobacter freundii 2526/96; 546
• In Vitro Model: Escherichia coli isolates; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: We have reported recently the DNA sequence of another Beta-lactamase, CTX- M-15, from Indian enterobacterial isolates that were resistant to both cefotaxime and ceftazidime.CTX-M-15 has a single amino acid change [Asp-240-Gly (Ambler numbering)]7 compared with CTX-M-3.

Key Molecule: Metallo-beta-lactamase (VIM1) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: A. xylosoxydans AX22 exhibited broad-spectrum resistance to Beta-lactams and aminoglycosides. The Beta-lactam resistance pattern (including piperacillin, ceftazidime, and carbapenem resistance) was unusual for this species, and the high-level carbapenem resistance suggested the production of an acquired carbapenemase. In fact, carbapenemase activity was detected in a crude extract of AX22 (specific activity, 184 +/- 12 U/mg of protein), and this activity was reduced (>80%) after incubation of the crude extract with 2 mM EDTA, suggesting the presence of a metallo-Beta-lactamase determinant.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Pyruvate decarboxylase 5 (PDC5) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Key Molecule: Pyruvate decarboxylase 3 (PDC3) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T97A
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Escherichia coli JM109; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Ceftibuten

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [15], [29]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ceftibuten
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Klebsiella pneumoniae strain HEL-1; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The phenotype of Klebsiella pneumoniae HEL-1 indicates a plasmidic cephamycinase gene (blaCMY-2),which is responsible for cephamycin resistance.

Ceftriaxone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [15], [17], [18]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Citrobacter freundii 2526/96; 546
• In Vitro Model: Escherichia coli isolates; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: We have reported recently the DNA sequence of another Beta-lactamase, CTX- M-15, from Indian enterobacterial isolates that were resistant to both cefotaxime and ceftazidime.CTX-M-15 has a single amino acid change [Asp-240-Gly (Ambler numbering)]7 compared with CTX-M-3.

Key Molecule: Beta-lactamase (BLA) [49]

• Resistant Disease: Enterobacter cloacae infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterobacter cloacae strains ENLA-1; 550
• In Vitro Model: Escherichia coli strain ECAA-1; 562
• In Vitro Model: Escherichia coli strain ECLA-1; 562
• In Vitro Model: Escherichia coli strain ECLA-2; 562
• In Vitro Model: Escherichia coli strain ECLA-4; 562
• In Vitro Model: Escherichia coli strain ECZK-1; 562
• In Vitro Model: Escherichia coli strain ECZP-1; 562
• In Vitro Model: Escherichia coli strain ECZU-1; 562
• In Vitro Model: Escherichia coli strain HK225f; 562
• In Vitro Model: Klebsiella pneumoniae strains KPAA-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPBE-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPGE-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPGE-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-10; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-3; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-4; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-5; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-6; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-7; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-8; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-9; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-10; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-11; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-12; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-13; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-4; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-6; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-7; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-8; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-9; 573
• In Vitro Model: Salmonella enterica serotype wien strain SWLA-1; 149384
• In Vitro Model: Salmonella enterica serotype wien strain SWLA-2; 149384
• Experiment for Molecule Alteration: Hybridization experiments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: Of 60 strains with reduced susceptibility to expanded-spectrum cephalosporins which had been collected, 34 (24Klebsiella pneumoniae, 7Escherichia coli, 1Enterobacter cloacae, and 2Salmonella entericaserotypewien) hybridized with the intragenic blaSHVprobe. TheblaSHVgenes were amplified by PCR, and the presence ofblaSHV-ESBLwas established in 29 strains by restriction enzyme digests of the resulting 1,018-bp amplimers as described elsewhere. These results were confirmed by the nucleotide sequencing of all 34 amplimers. Five strains contained SHV non-ESBL enzymes.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: TolC family outer membrane protein (TOLC) [10]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AYE WT; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO Omega abuO; 509173
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: AbuO, an OMP, confers broad-spectrum antimicrobial resistance via active efflux in A. baumannii.

Cefuroxime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [42]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Y221H
• Resistant Drug: Cefuroxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli EC13; 562
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: Disk diffusion test assay
• Mechanism Description: The CMY-136 Beta-lactamase, a Y221H point mutant derivative of CMY-2,confers an increased level of resistance to ticarcillin, cefuroxime, cefotaxime, and ceftolozane/tazobactam.

Key Molecule: Beta-lactamase (BLA) [21]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cefuroxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• Experiment for Molecule Alteration: DNA sequencing and protein assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: P. aeruginosa harbors two naturally encoded Beta-lactamase genes, one of which encodes an inducible cephalosporinase and the other of which encodes a constitutively expressed oxacillinase. AmpC is a kind of cephalosporinase which lead to drug resistance.

Key Molecule: Beta-lactamase (BLA) [16], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Cefuroxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli Gre-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The first extended-spectrum Beta-lactamase (ESBL) of the CTX-M type (MEN-1/CTX-M-1) was reported at the beginning of the 1990s.CTX-M-27 differed from CTX-M-14 only by the substitution D240G and was the third CTX-M enzyme harbouring this mutation after CTX-M-15 and CTX-M-16. The Gly-240-harbouring enzyme CTX-M-27 conferred to Escherichia coli higher MICs of ceftazidime (MIC, 8 versus 1 mg/L) than did the Asp-240-harbouring CTX-M-14 enzyme.

Cephalexin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [34]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cephalexin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM 160(Y); 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM158; 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM159; 1063
• Experiment for Molecule Alteration: Sodium dodecyl sulfate-PAGE assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Thirteen strains of the gram-negative, facultative phototrophic bacterium Rhodobacter sphaeroides were examined fro susceptibility to beta-lactam antibiotics. All strains were sensitive to the semisynthetic penicillins ampicillin, carbenicillin, oxacillin, cloxacillin, and methicillin, but 10 of the 13 strains were resistant to penicillin G, as well as a number of cephalosporins, such as cephalothin, cephapirin, and cephalosporin C. A beta-lactamase (EC 3.5.2.6) with strong cephalosporinase activity was detected in all of the resistant strains of R. sphaeroides. With strain Y-1 as a model, it was shown that the beta-lactamase was inducible by penicillin G, cephalosporin C, cephalothin, and to some minor extent, cephapirin.

Cephaloridine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [21]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cephaloridine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• Experiment for Molecule Alteration: DNA sequencing and protein assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: P. aeruginosa harbors two naturally encoded Beta-lactamase genes, one of which encodes an inducible cephalosporinase and the other of which encodes a constitutively expressed oxacillinase. AmpC is a kind of cephalosporinase which lead to drug resistance.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Outer membrane porin C (OMPC) [37], [38], [39]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cephaloridine
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli 1422; 562
• In Vitro Model: Escherichia coli 1437; 562
• In Vitro Model: Escherichia coli B1343; 562
• In Vitro Model: Escherichia coli B1350; 562
• In Vitro Model: Escherichia coli B1421; 562
• In Vitro Model: Escherichia coli pop1010; 562
• Experiment for Drug Resistance: Disk diffusion test assay
• Mechanism Description: Permeability of the outer membrane to lowmolecular-weight hydrophilic molecules is due to the presence of porin protein molecules such as OmpF and OmpC, which form pores in the outer membrane that allow small molecules to diffuse rapidly into the periplasmic space.The case of cephaloridine and cefazolin is remarkable because mutants lacking the OmpF or the OmpC proteins individually were as susceptible to cefaloridine and cefazolin as was the wild type, but mutants lacking both proteins were resistant to these Beta-lactams.

Cephalosporin C

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [34]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cephalosporin C
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM 160(Y); 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM158; 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM159; 1063
• Experiment for Molecule Alteration: Sodium dodecyl sulfate-PAGE assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Thirteen strains of the gram-negative, facultative phototrophic bacterium Rhodobacter sphaeroides were examined fro susceptibility to beta-lactam antibiotics. All strains were sensitive to the semisynthetic penicillins ampicillin, carbenicillin, oxacillin, cloxacillin, and methicillin, but 10 of the 13 strains were resistant to penicillin G, as well as a number of cephalosporins, such as cephalothin, cephapirin, and cephalosporin C. A beta-lactamase (EC 3.5.2.6) with strong cephalosporinase activity was detected in all of the resistant strains of R. sphaeroides. With strain Y-1 as a model, it was shown that the beta-lactamase was inducible by penicillin G, cephalosporin C, cephalothin, and to some minor extent, cephapirin.

Cephapirin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [34]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Cephapirin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM 160(Y); 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM158; 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM159; 1063
• Experiment for Molecule Alteration: Sodium dodecyl sulfate-PAGE assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Thirteen strains of the gram-negative, facultative phototrophic bacterium Rhodobacter sphaeroides were examined fro susceptibility to beta-lactam antibiotics. All strains were sensitive to the semisynthetic penicillins ampicillin, carbenicillin, oxacillin, cloxacillin, and methicillin, but 10 of the 13 strains were resistant to penicillin G, as well as a number of cephalosporins, such as cephalothin, cephapirin, and cephalosporin C. A beta-lactamase (EC 3.5.2.6) with strong cephalosporinase activity was detected in all of the resistant strains of R. sphaeroides. With strain Y-1 as a model, it was shown that the beta-lactamase was inducible by penicillin G, cephalosporin C, cephalothin, and to some minor extent, cephapirin.

Chloramphenicol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Chloramphenicol acetyltransferase (CAT) [50]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Paenibacillus sp. LC231; 1120679
• Mechanism Description: Redundant chloramphenicol (catV and clbB) and kanamycin (ant(4')-lc and aac(6')-35) resistance are common in Paenibacillaceae, especially within Brevibacillus and Aneurinibacillus.

Key Molecule: Chloramphenicol acetyltransferase (CAT) [35]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Paenibacillus sp. LC231; 1120679
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: CatU inactivates chloramphenicol by acetylation.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [22]

• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Key Molecule: Chloramphenicol acetyltransferase (CAT) [51]

• Resistant Disease: Enterococcus faecalis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Escherichia coli strain XL-1 Blue; 562
• In Vitro Model: Enterococcus faecalis ESP91; 1351
• In Vitro Model: Enterococcus faecalis FO1; 1351
• In Vitro Model: Enterococcus faecalis FO5; 1351
• In Vitro Model: Enterococcus faecalis JHBURE16-1; 1351
• In Vitro Model: Enterococcus faecalis JHBURE16-2; 1351
• In Vitro Model: Enterococcus faecalis JHBURE16-3; 1351
• In Vitro Model: Enterococcus faecalis JHBURE8-1; 1351
• In Vitro Model: Enterococcus faecalis JHBURE8-2; 1351
• In Vitro Model: Enterococcus faecalis JHBURE8-3; 1351
• In Vitro Model: Enterococcus faecalis JHRE25-2; 1351
• In Vitro Model: Enterococcus faecalis JHRE25-3; 1351
• In Vitro Model: Enterococcus faecalis RE17; 1351
• In Vitro Model: Enterococcus faecalis RE25; 1351
• In Vitro Model: Enterococcus faecalis RE38; 1351
• In Vitro Model: Enterococcus faecalis RE44; 1351
• In Vitro Model: Enterococcus faecalis RE52; 1351
• In Vitro Model: Enterococcus faecium FI1; 1352
• In Vitro Model: Escherichia coli CM1; CM25
• In Vitro Model: Escherichia coli CM2; CM25
• In Vitro Model: Escherichia coli CM25; 562
• In Vitro Model: Lactococcus lactis susp. cremoris AC1; 1359
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis Bu2-60; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis Bu2-60/pAMb1; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis Bu2-60/pIP501; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis Bu2-60/pRE39; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis BURE25-11; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis BURE25-12; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis BURE25-15; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis BURE25-16; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis BURE25-3; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis BURE25-6; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis BURE25-7; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis BURE25-8; 44688
• In Vitro Model: Lactococcus lactis susp. lactis biovar. diacetylactis BURE25-9; 44688
• In Vitro Model: Listeria innocua L19; 1642
• In Vitro Model: Listeria innocua L191; 1642
• In Vitro Model: Listeria innocua L193; 1642
• In Vitro Model: Staphylococcus xylosus strains VF5; 1288
• Experiment for Molecule Alteration: DNA hybridizations assay
• Experiment for Drug Resistance: Microdilution test assay
• Mechanism Description: Two antibiotic-resistance genes are present on this 30.5-kb region, a chloramphenicol acetyltransferase gene (orf10) and a 23S rRNA methyltransferase gene (orf14). Both genes have been shown to be active in E. faecalis RE25 and in its transconjugants.

Key Molecule: CATB6 chloramphenicol acetyltransferase (CATB6) [52]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Pseudomonas aeruginosa strain 101/1477; 287
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: The third gene cassette is 730 bp long and contains an open reading frame (ORF) potentially encoding a protein that exhibits a high degree of sequence similarity to members of the CATB lineage of chloramphenicol acetyltransferases. The new catB allele appeared to be functional since both DH5alpha(pPAM-101) and DH5alpha(pkAM-36BE) showed a decreased chloramphenicol susceptibility and was named catB6.

Key Molecule: Chloramphenicol acetyltransferase (CAT) [53]

• Resistant Disease: Lactobacillus reuteri infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Escherichia coli strain CSR 603; 562
• In Vitro Model: Escherichia coli strain DH5a-CR17; 668369
• In Vitro Model: Escherichia coli strain DH5a-CR36; 668369
• In Vitro Model: Lactobacillus reuteri strain DSM 20016; 557436
• In Vitro Model: Lactobacillus reuteri strain DSM 20016-CR3; 557436
• In Vitro Model: Lactobacillus reuteri strain G4; 1598
• In Vitro Model: Lactobacillus reuteri strain G4-CS1-3; 1598
• Experiment for Molecule Alteration: Hybridization assay
• Mechanism Description: Lactobacillus reuteri G4 contains a 7.0-kb plasmid (pTC82) encoding resistance to chloramphenicol (Cm). Determination of the nucleotide sequence of the genetic determinant (cat-TC) encoding resistance to Cm on pTC82 revealed an open reading frame for a 238-amino-acid Cm acetyltransferase (CAT) monomer. This is the first reported nucleotide sequence of a Cm-resistance determinant from L. reuteri and also the first evidence of adding Lactobacillus to the list of versatile bacterial genera which naturally acquire the cat-pC194 gene in the microbial ecological system.

Key Molecule: Chloramphenicol acetyltransferase (CAT) [54]

• Resistant Disease: Proteus mirabilis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain JM103; 83333
• In Vitro Model: Proteus mirabilis strain PM13; 584
• In Vitro Model: Proteus mirabilis strain PM2; 584
• Experiment for Molecule Alteration: RNA-DNA hybridizations assay
• Mechanism Description: In Proteus mirabilis PM13 chloramphenicol resistance is mediated by the cat gene, a single copy of which is present in both resistant and sensitive isolates and which reverts at a high frequency. RNA measurements show an about 8.5-fold increase in cat-specific mRNA in cells expressing the resistance phenotype as compared with those which are sensitive to chloramphenicol.

Key Molecule: Chloramphenicol acetyltransferase 2 (CATII) [55]

• Resistant Disease: Haemophilus influenzae infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain JM 101; 562
• Mechanism Description: Bacterial resistance to the antibiotic chloramphenicol, an inhibitor of the peptidyltransferase activity of prokaryotic ribosomes, is commonly conferred by the enzyme chloramphenicol acetyltransferase (CAT,EC2.3.1.28). The enzyme catalyses transfer of the acetyl group of acetyl-CoA to the primary (C-3) hydroxy group of chloramphenicol, yielding 3-acetylchloramphenicol, which fails to bind to bacterial ribosomes. Three classes of CAT variant have been characterized among Gram-negative bacteria, designated typesI, II and III.

Key Molecule: Chloramphenicol acetyltransferase (CAT) [56]

• Resistant Disease: Clostridium perfringens infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Clostridium perfringens strain CW531; 1502
• Experiment for Molecule Alteration: Double-stranded dideoxy-chain termination method assay
• Mechanism Description: The enzyme chloramphenicol acetyltransferase (CAT) mediates the inactivation of the antibiotic chloramphenicol, a potent inhibitor of prokaryotic peptidyltransferase activity. The active CAT enzyme, which catalyzes the acetyl coenzyme A-dependent acetylation of chloramphenicol, is a trimer of identical subunits of approximately 25 kDa. The nucleotide sequence of the Clostridium perfringens chloramphenicol acetyltransferase (CAT)-encoding resistance determinant, catQ, was determined. Phylogenetic analysis revealed that the CATQ monomer was as closely related to CAT proteins from Staphylococcus aureus and Campylobacter coli as it was to CAT monomers from the clostridia.

Key Molecule: Chloramphenicol acetyltransferase (CAT) [57]

• Resistant Disease: Agvobactevitlm tumefuciens infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Agrobacterium tumefaciens strain C58; 358
• In Vitro Model: Escherichia coli strain JM101; 83333
• Experiment for Molecule Alteration: Enzyme assay
• Mechanism Description: The nucleotide sequence of a chloramphenicol-resistance (CmR) determinant from the Gram- soil bacterium Agrobacterium tumefaciens was determined, and its gene product was identified as Cm acetyltransferase (CAT). Comparison of the amino acid sequences of the A. tumefaciens CAT and various CAT proteins of Gram+ and Gram- origin shows no homology between this and the other enzymes.

Key Molecule: Chloramphenicol acetyltransferase (CAT) [58]

• Resistant Disease: Clostridium butyricum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• Experiment for Molecule Alteration: Nucleotide sequence assay
• Mechanism Description: Bacterial resistance to chloramphenicol is most commonly mediated by production of the enzyme chloramphenicol acetyltransferase (CAT), which catalyzes the transfer of an acetyl group from acetyl coenzyme A to the primary hydroxyl group of chloramphenicol (O-acetylation). The O-acetoxy derivatives of chloramphenicol do not bind to bacterial ribosomes and are consequently devoid of antimicrobial activity. The five distinct clostridial cat genes that have been cloned include catP and catQ from C. perfringens, catD from Clostridium dificile, and catA and catB from C. butyricum. The C. perfringens genes catP and catQ and the C. difficile gene catD have been sequenced.

Key Molecule: Chloramphenicol acetyltransferase (CAT) [59]

• Resistant Disease: Vibrio anguillarum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain CSR603; 562
• In Vitro Model: Escherichia coli strain HBIOI; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The chloramphenicol resistant genes (cat) have been found in various bacterial chromosomes, in antibioticresistant (R) plasmids and sometimes within a transposable element.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug transporter MdfA (MDFA) [60], [61]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli C43 (DE3); 562
• Mechanism Description: Being one of the best-characterized bacterial MFS antiporters biochemically, MdfA from Escherichia coli (ecMdfA) is known to confer resistance to a variety of structurally distinct cationic and zwitterionic lipophilic compounds, as well as to a number of electroneutral antibiotics of clinical importance.

Key Molecule: Chloramphenicol resistance protein (CMX) [62], [63]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli S17-1; 1227813
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• In Vitro Model: Corynebacterium glutamicum CX61; 1718
• In Vitro Model: Corynebacterium glutamicum CX73; 1718
• In Vitro Model: Corynebacterium glutamicum RM3; 1718
• In Vitro Model: Escherichia coli DH5alphaMCR; 668369
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The central region of Tn5564 encodes the chloramphenicol resistance gene cmx, specifying a transmembrane chloramphenicol efflux protein, and an open reading frame homologous to transposases of insertion sequences identified in Arthrobacter nicotinovorans and Bordetella pertussis.

Key Molecule: ARE-ABC-F family resistance factor PoxtA (POXTA) [64]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Escherichia coli Mach1 T1R; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth dilution test assay
• Mechanism Description: The poxtA gene encodes a protein that is 32% identical to OptrA and exhibits structural features typical of the F lineage of the ATP-binding cassette (ABC) protein superfamily that cause antibiotic resistance by ribosomal protection.

Key Molecule: Protein pexA (PEXA) [65]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• Experiment for Molecule Alteration: Nucleotide sequence assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: In its natural host, pexA could provide protection against chloramphenicol and florfenicol excreted by Streptomyces spp.

Key Molecule: Bcr/CflA family efflux transporter (BCML) [40]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Pseudomonas aeruginosa PU21; 287
• In Vitro Model: Escherichia coli strain k-12 C600; 83333
• In Vitro Model: Pseudomonas aeruginosa 104116; 287
• In Vitro Model: Pseudomonas aeruginosa SOF-1; 287
• Experiment for Molecule Alteration: Southern technique assay
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: An additional ORF located downstream corresponded to a cmlA-like gene that encodes CMLA6 for chloramphenicol resistance and that shared 99% amino acid identity with CMLA1, with only three amino acid changes.

Key Molecule: Bcr/CflA family efflux transporter (BCML) [66]

• Resistant Disease: Enterobacter aerogenes infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM83; 562
• In Vitro Model: Enterobacter aerogenes strain; 548
• In Vitro Model: Enterobacter aerogenes strain BM2688; 548
• In Vitro Model: Enterobacter aerogenes strain BM2688-1; 548
• In Vitro Model: Escherichia coli strain J5-3; 562
• Experiment for Molecule Alteration: Southern hybridization assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: A putative GTG initiation codon at position 718 was preceded at 8 bp by a RBS-like sequence. This coding sequence, designated cmlA2, shared 83.7% identity with the cmlA1 gene of the class 1 integron In4 in Tn1696 which confers nonenzymatic chloramphenicol resistance.

Key Molecule: Chloramphenicol resistance protein (Tn5561-Unclear) [67]

• Resistant Disease: Rhodococcus erythropolis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Rhodococcus erythropolis strain SQ1; 1833
• Experiment for Molecule Alteration: Southern hybridization assay
• Mechanism Description: Three copies of the IS21-related transposable element IS1415 were identified in Rhodococcus erythropolis NI86/21. Adjacent to one of the IS1415 copies, a 47-bp sequence nearly identical to the conserved 5* end of integrons was found. Accurate transposition of IS1415 carrying a chloramphenicol resistance gene (Tn5561) was demonstrated following delivery from a suicide vector to R. erythropolis SQ1.

Key Molecule: Multidrug transporter MdfA (MDFA) [68]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli MC1061; 1211845
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Bacillus subtilis strain BR151; 1423
• In Vitro Model: Rhodococcus fascians strain D188-5; 2022521
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Rhodococcus fascians NCPPB 1675 (located on the conjugative plasmid pRF2) allowed the identification of two possible open reading frames (ORFs), of which ORF1 was consistent with the mutational analysis. Biochemical analysis of cmr revealed that it does not encode an antibiotic-modifying enzyme. The amino acid sequence of ORF1 predicted a hydrophobic protein, with 12 putative membrane-spanning domains, homologous to proteins involved in the efflux of tetracycline across the plasma membrane.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Enterococcal surface protein (ESP) [69]

• Resistant Disease: Enterococci faecium infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis strain JH2-2; 1320322
• In Vitro Model: Enterococcus faecalis strain pIP1326g; 1351
• In Vitro Model: Enterococcus faecalis strain pIP655; 1351
• In Vitro Model: Enterococcus faecalis strain pIP683; 1351
• In Vitro Model: Enterococcus faecalis strain pIP687; 1351
• In Vitro Model: Enterococcus faecium strain pIP1182; 1352
• In Vitro Model: Enterococcus faecium strain pIP1535; 1352
• In Vitro Model: Enterococcus faecium strain pIP1538; 1352
• In Vitro Model: Enterococcus faecium strain pIP1539; 1352
• In Vitro Model: Enterococcus faecium strain pIP1687; 1352
• In Vitro Model: Enterococcus faecium strain pIP713; 1352
• In Vitro Model: Streptococci strain A451; 36470
• In Vitro Model: Streptococci strain A453; 36470
• In Vitro Model: Streptococci strain A456; 36470
• In Vitro Model: Streptococci strain B109; 1319
• In Vitro Model: Streptococci strain B117; 1319
• In Vitro Model: Streptococci strain B118; 1319
• In Vitro Model: Streptococci strain B120; 1319
• In Vitro Model: Streptococci strain B126; 1319
• In Vitro Model: Streptococci strain B127; 1319
• In Vitro Model: Streptococci strain BM132; 1319
• In Vitro Model: Streptococci strain BM137; 36470
• In Vitro Model: Streptococci strain BM140; 1319
• In Vitro Model: Streptococci strain G44; 1320
• In Vitro Model: Streptococci strain G52; 1320
• In Vitro Model: Streptococci strain G54; 1320
• Experiment for Molecule Alteration: Southern blotting assay
• Mechanism Description: An assay based on the utilization of degenerate primers that enable enzymatic amplification of an internal fragment of cat genes known to be present in gram-positive cocci was developed to identify the genes encoding chloramphenicol resistance in streptococci and enterococci. The functionality of this system was illustrated by the detection of cat genes belonging to four different hydridization classes represented by the staphylococcal genes catpC221, catpC194, catpSCS7, and the clostridial gene catP, and by the characterization of a new streptococcal cat gene designated catS.

Key Molecule: Enterococcal surface protein (ESP) [69]

• Resistant Disease: Enterococci faecalisc infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis strain JH2-2; 1320322
• In Vitro Model: Enterococcus faecalis strain pIP1326g; 1351
• In Vitro Model: Enterococcus faecalis strain pIP655; 1351
• In Vitro Model: Enterococcus faecalis strain pIP683; 1351
• In Vitro Model: Enterococcus faecalis strain pIP687; 1351
• In Vitro Model: Enterococcus faecium strain pIP1182; 1352
• In Vitro Model: Enterococcus faecium strain pIP1535; 1352
• In Vitro Model: Enterococcus faecium strain pIP1538; 1352
• In Vitro Model: Enterococcus faecium strain pIP1539; 1352
• In Vitro Model: Enterococcus faecium strain pIP1687; 1352
• In Vitro Model: Enterococcus faecium strain pIP713; 1352
• In Vitro Model: Streptococci strain A451; 36470
• In Vitro Model: Streptococci strain A453; 36470
• In Vitro Model: Streptococci strain A456; 36470
• In Vitro Model: Streptococci strain B109; 1319
• In Vitro Model: Streptococci strain B117; 1319
• In Vitro Model: Streptococci strain B118; 1319
• In Vitro Model: Streptococci strain B120; 1319
• In Vitro Model: Streptococci strain B126; 1319
• In Vitro Model: Streptococci strain B127; 1319
• In Vitro Model: Streptococci strain BM132; 1319
• In Vitro Model: Streptococci strain BM137; 36470
• In Vitro Model: Streptococci strain BM140; 1319
• In Vitro Model: Streptococci strain G44; 1320
• In Vitro Model: Streptococci strain G52; 1320
• In Vitro Model: Streptococci strain G54; 1320
• Experiment for Molecule Alteration: Southern blotting assay
• Mechanism Description: An assay based on the utilization of degenerate primers that enable enzymatic amplification of an internal fragment of cat genes known to be present in gram-positive cocci was developed to identify the genes encoding chloramphenicol resistance in streptococci and enterococci. The functionality of this system was illustrated by the detection of cat genes belonging to four different hydridization classes represented by the staphylococcal genes catpC221, catpC194, catpSCS7, and the clostridial gene catP, and by the characterization of a new streptococcal cat gene designated catS.

Chlortetracycline

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tetracycline resistance protein Tet (TETW/N/W) [70]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Chlortetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli EPI-300; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Tet(W/N/W) encodes mosaic ribosomal protection(since tetracyclines bind to the 30S ribosomal subunit to inhibit protein translation) and induces resistance.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Tetracycline resistance protein tet(59) (TET59) [70]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Chlortetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli EPI-300; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Tet(59) is preceded by a homolog of the tetracycline repressor tetR typically found upstream of tet genes encoding efflux pumps and include the two palindromic operator sequences present in all regulatory regions of the tet(A)-tet(R) family (33), suggesting that tet(59) probably belongs to the efflux pump family.

Ciprofloxacin XR

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA gyrase subunit A (GYRA) [71], [72]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T83I
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa ATCC10145; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: The major mechanism of the resistance of this Pseudomonas aeruginosa to fluoroquinolones is the modification of type II topoisomerases (DNA gyrase and topoisomerase IV).

Key Molecule: DNA gyrase subunit A (GYRA) [71], [72]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.H83R
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa ATCC10145; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: The major mechanism of the resistance of this Pseudomonas aeruginosa to fluoroquinolones is the modification of type II topoisomerases (DNA gyrase and topoisomerase IV).

Key Molecule: DNA gyrase subunit A (GYRA) [73]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83L; p.S80L
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• Experiment for Molecule Alteration: ERIC-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Mutations that occur in gyrA and parC genes were detected by DNA sequence analysis in 16 resistant strains representing each clone and subtype.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [73]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83L; p.S80L
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• Experiment for Molecule Alteration: ERIC-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Mutations that occur in gyrA and parC genes were detected by DNA sequence analysis in 16 resistant strains representing each clone and subtype.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [74]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S463A
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [74]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S464Y
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [74]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S80I
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83L
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-112; 562
• In Vitro Model: Escherichia coli strain N-118; 562
• In Vitro Model: Escherichia coli strain N-119; 562
• In Vitro Model: Escherichia coli strain N-51; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83W
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-18; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D87N
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-113; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.G81C
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-97; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A84P
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-5; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A67S
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-10; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Q106H
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-89; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Quinolone efflux pump (QEPA2) [78]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A99G+p.V134I
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: QepA confers decreased susceptibility to hydrophilic fluoroquinolones (e.g., norfloxacin, ciprofloxacin, and enrofloxacin) with a 32- to 64-fold increase of MICs.

Clarithromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase ermE (ERME) [79], [80], [81]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Clarithromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli AS19-RrmA-; 562
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli JC7623; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Methylation of specific nucleotides in rRNA is one of the means by which bacteria achieve resistance to macrolides-lincosamides-streptogramin B (MLSB) and ketolide antibiotics.ErmE dimethylation confers high resistance to all the MLSB and ketolide drugs.

Key Molecule: erm(X)cj (Unclear) [82]

• Resistant Disease: Corynebacterium jeikeium infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Frameshift mutation; Codon 216 frame shift
• Resistant Drug: Clarithromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Corynebacterium diphtheriae isolate; 1717
• In Vitro Model: Corynebacterium glutamicum kO8; 1718
• In Vitro Model: Corynebacterium jeikeium isolates; 38289
• In Vitro Model: Escherichia coli ATCC 25923; 562
• In Vitro Model: Escherichia coli strain XL1-Blue MRF9; 562
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion methods assay; agar dilution methods assay
• Mechanism Description: Abundant amplificationproducts of slightly less than 400 bp were generated from DNAisolated from the 17 MLSb-resistant strains, whereas no am-plification products were generated with the DNA isolatedfrom the three susceptible strains. The DNA sequences of the amplification products showed 95% identity to the erm(X) gene isolated from a C. xerosis strain,erm(X)cx or ermCX. Thus, MLSb resistance in C. jeikeiumis associated with the presence of an allele, erm(X)cj, of the class Xermgenes. The first 215 amino acids of the predicted polypeptides for strains CJ12 and CJ21 are 93.5 and 98.6% identical to Erm(X)cx, the Erm protein from C. xerosi. The major difference between the two Erm(X)cj polypeptides and the Erm(X)cx polypeptide is a frame shift within codon 216. This results in the Erm(X)cj polypeptides being 31 amino acids longer than Erm(X)cx.

Clindamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase ermE (ERME) [79], [80], [81]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Clindamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli AS19-RrmA-; 562
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli JC7623; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Methylation of specific nucleotides in rRNA is one of the means by which bacteria achieve resistance to macrolides-lincosamides-streptogramin B (MLSB) and ketolide antibiotics.ErmE dimethylation confers high resistance to all the MLSB and ketolide drugs.

Key Molecule: Probable dual-specificity RNA methyltransferase RlmN (RLMN ) [35]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Clindamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Paenibacillus sp. LC231; 1120679
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A clindamycin resistance gene relates to the Rlmk 23S ribosomal RNA methyltransferase COG family.Clindamycin targets the peptidyltransferase centre and inhibits protein synthesis by interfering with transfer RNA binding at the A-site.

Key Molecule: Ribosomal RNA large subunit methyltransferase Cfr (CFRB) [83]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; c.2576G>T
• Resistant Drug: Clindamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Enterococcus faecium ATCC 29212; 1352
• In Vitro Model: Enterococcus faecium ATCC 35667; 1352
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Cfr methylates the unreactive C2- and C8-carbon atoms on the A2503 residue located in a functionally critical region of the 23S rRNA component.The methylation at C8 protects the Cfr-producing bacteria from the action of five major classes of antibiotics, namely, phenicols, oxazolidinones, pleuromutilins, macrolides, and streptogramin A compounds (PhLOPSA phenotype).

Key Molecule: Carboxymethylenebutenolidase (CLCD) [84]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Clindamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli AS19; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The Cfr RNA methyltransferase causes multiple resistances to peptidyl transferase inhibitors by methylation of A2503 23S rRNA.clcD codes the same enzyme.

Key Molecule: Ribosomal RNA large subunit methyltransferase (CFR ) [85]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Clindamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Cfr confers resistance to antibiotics binding to the peptidyl transferase center on the ribosome.The primary product of the Cfr-mediated methylation is 8-methyladenosine (m8A), a new natural RNA modification that has so far not been seen at sites other than A2503 in 23S rRNA.

Key Molecule: 23S rRNA (Adenine(2503)-C(8))-methyltransferase ClbA (CIBA) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Clindamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Key Molecule: 23S ribosomal RNA methyltransferase Erm36 (ERM36) [87]

• Resistant Disease: Micrococcus luteus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Clindamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Micrococcus luteus MAW843; 1270
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar diffusion test assay
• Mechanism Description: Erm(36) was most related (about 52-54% identity) to erythromycin-resistance proteins found in high-G+C Gram-positive bacteria and lead to drug resistance.

Key Molecule: erm(X)cj (Unclear) [82]

• Resistant Disease: Corynebacterium jeikeium infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Frameshift mutation; Codon 216 frame shift
• Resistant Drug: Clindamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Corynebacterium diphtheriae isolate; 1717
• In Vitro Model: Corynebacterium glutamicum kO8; 1718
• In Vitro Model: Corynebacterium jeikeium isolates; 38289
• In Vitro Model: Escherichia coli ATCC 25923; 562
• In Vitro Model: Escherichia coli strain XL1-Blue MRF9; 562
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion methods assay; agar dilution methods assay
• Mechanism Description: Abundant amplificationproducts of slightly less than 400 bp were generated from DNAisolated from the 17 MLSb-resistant strains, whereas no am-plification products were generated with the DNA isolatedfrom the three susceptible strains. The DNA sequences of the amplification products showed 95% identity to the erm(X) gene isolated from a C. xerosis strain,erm(X)cx or ermCX. Thus, MLSb resistance in C. jeikeiumis associated with the presence of an allele, erm(X)cj, of the class Xermgenes. The first 215 amino acids of the predicted polypeptides for strains CJ12 and CJ21 are 93.5 and 98.6% identical to Erm(X)cx, the Erm protein from C. xerosi. The major difference between the two Erm(X)cj polypeptides and the Erm(X)cx polypeptide is a frame shift within codon 216. This results in the Erm(X)cj polypeptides being 31 amino acids longer than Erm(X)cx.

Key Molecule: ErmR rRNA adenine N6-methyltransferase (ERMR) [88]

• Resistant Disease: Aeromicrobium erythreum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Clindamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Aeromicrobium erythreum strains AR18; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1807; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1848; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1849; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1850; 2041
• In Vitro Model: Aeromicrobium erythreum strains BD170; 2041
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: Using the Ery- strain AR1807 as a recipient for plasmid-directed integrative recombination, the chromosomal ermR gene (encoding 23S rRNA methyltransferase) was disrupted, ermR-disrupted strains AR1848 and AR1849 were highly sensitive to erythromycin and the other macrolide antibiotics. Phenotypic characterizations demonstrated that ermR is the sole determinant of macrolide antibiotic resistance in A. erythreum. AR18, AR1807, and AR1850 (Ery- Ermr) were resistant to clindamycin, erythromycin, spiramycin, and tylosin (some sensitivity totylosin was observed at high concentrations).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter ATP-binding protein (ABCP) [89], [90]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T450I
• Resistant Drug: Clindamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Enterococcus faecium HM1070; 1352
• In Vitro Model: Enterococcus faecium UCN80; 1352
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: ABC systems constitute one of the largest families of proteins, with most of them being involved in import and export, often called ABC transporters.Several of these class 2 ABC systems have been involved in MLS resistance, such as Msr-, Vga-, or Lsa-like proteins.The observed profile of cross-resistance to lincosamides, streptogramins A, and pleuromutilins conferred by Eat(A)v was similar to those conferred by other Lsa-like proteins.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Colibactin polyketide synthase ClbC (CLBC) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Clindamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Co-trimoxazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside acetyltransferase (AAC) [22]

• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Co-trimoxazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Colistin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Colistin resistance PEtN transferase (ICRMc ) [91]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Colistin A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BW25113; 679895
• Mechanism Description: Diverse covalent modifications of LPS, which include among others the addition of phosphoethanolamine (PEtN) groups are thought to alter the physical properties of the outer membrane, resulting in polymyxin resistance. The increased clinical and agricultural use of colistin has been linked to the mobilization and transfer of colistin resistance elements to human pathogenic bacteria.53 resistance elements to human pathogenic bacteria.

Colistin B

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Colistin resistance PEtN transferase (ICRMc ) [91]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Colistin B
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BW25113; 679895
• Mechanism Description: Diverse covalent modifications of LPS, which include among others the addition of phosphoethanolamine (PEtN) groups are thought to alter the physical properties of the outer membrane, resulting in polymyxin resistance. The increased clinical and agricultural use of colistin has been linked to the mobilization and transfer of colistin resistance elements to human pathogenic bacteria.53 resistance elements to human pathogenic bacteria.

Dalfopristin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter ATP-binding protein (ABCP) [89], [90]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T450I
• Resistant Drug: Dalfopristin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Enterococcus faecium HM1070; 1352
• In Vitro Model: Enterococcus faecium UCN80; 1352
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: ABC systems constitute one of the largest families of proteins, with most of them being involved in import and export, often called ABC transporters.Several of these class 2 ABC systems have been involved in MLS resistance, such as Msr-, Vga-, or Lsa-like proteins.The observed profile of cross-resistance to lincosamides, streptogramins A, and pleuromutilins conferred by Eat(A)v was similar to those conferred by other Lsa-like proteins.

Daptomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Sensor protein kinase WalK (WALK) [92], [93]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S221P
• Resistant Drug: Daptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MW2; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1616; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1617; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1618; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CiproR; 1242971
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The exact mechanism by which the changes in YycG alter the protein's function is not known. Martin et al. suggested that yycF and yycG are involved in cell permeability and showed that loss of yycF activity results in increased susceptibility to macrolide and lincosamide antibiotics and unsaturated long-chain fatty acids.

Key Molecule: Sensor protein kinase WalK (WALK) [92], [93]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.R263C
• Resistant Drug: Daptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MW2; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1616; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1617; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1618; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CiproR; 1242971
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The exact mechanism by which the changes in YycG alter the protein's function is not known. Martin et al. suggested that yycF and yycG are involved in cell permeability and showed that loss of yycF activity results in increased susceptibility to macrolide and lincosamide antibiotics and unsaturated long-chain fatty acids.

Key Molecule: Sensor protein kinase WalK (WALK) [92], [93]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; c.26121insA
• Resistant Drug: Daptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MW2; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1616; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1617; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1618; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CiproR; 1242971
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The exact mechanism by which the changes in YycG alter the protein's function is not known. Martin et al. suggested that yycF and yycG are involved in cell permeability and showed that loss of yycF activity results in increased susceptibility to macrolide and lincosamide antibiotics and unsaturated long-chain fatty acids.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione biosynthesis bifunctional protein GshAB (GSHAB ) [94]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.E354K
• Resistant Drug: Daptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: As a glutathione synthase, GshF has previously been implicated in the oxidative stress response across multiple species. GshF is commonly found among mammalian pathogens and could have a role in mitigating DNA damage caused by general oxidative. stress.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Transcriptional regulatory protein LiaR (LIAR) [94]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D191N
• Resistant Drug: Daptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: LiaFSR is a component of the CESR regulon and responds to changes in cell envelope integrity by regulating downstream genes to counteract damage.LiaFSR mutations occurred in liaF (78%), with changes in yvlB (12%) and liaR (4%) comprising the remainder.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette transporter A (ABCA) [95], [96], [97]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Daptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Staphylococcus aureus MW2; 1242971
• In Vivo Model: Swiss webster male mice model; Mus musculus
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The ATP-dependent transporter gene abcA in Staphylococcus aureus confers resistance to hydrophobic Beta-lactams.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatidate cytidylyltransferase (CDSA) [98]

• Resistant Disease: Streptococcus mitis/oralis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D222N
• Resistant Drug: Daptomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptococcus mitis isolates; 28037
• In Vitro Model: Streptococcus oralis isolates; 1303
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Mechanism Description: Mutation changes in CdsA cause daptomycin resistance in S. mitis/oralis.

Key Molecule: Cardiolipin synthase (CLS) [94], [99], [100]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.R218Q
• Resistant Drug: Daptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecium S447; 1134840
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Mol00855
• Mechanism Description: Mutations in genes encoding proteins associated with cell envelope homeostasis (yycFG and liaFSR) and phospholipid metabolism (cardiolipin synthase [cls] and cyclopropane fatty acid synthetase [cfa]) were investigated in daptomycin resistance derivatives.

Key Molecule: Cardiolipin synthase (CLS) [94], [99], [100]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.R267H
• Resistant Drug: Daptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecium S447; 1134840
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Mol00855
• Mechanism Description: Mutations in genes encoding proteins associated with cell envelope homeostasis (yycFG and liaFSR) and phospholipid metabolism (cardiolipin synthase [cls] and cyclopropane fatty acid synthetase [cfa]) were investigated in daptomycin resistance derivatives.

Key Molecule: Cardiolipin synthase (CLS) [94], [99], [100]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Frameshift mutation; p.NFQ77-79del
• Resistant Drug: Daptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecium S447; 1134840
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Mol00855
• Mechanism Description: Mutations in genes encoding proteins associated with cell envelope homeostasis (yycFG and liaFSR) and phospholipid metabolism (cardiolipin synthase [cls] and cyclopropane fatty acid synthetase [cfa]) were investigated in daptomycin resistance derivatives.

Dibekacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(6')-acetyltransferase type 1 (A6AC1) [3]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dibekacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa Nk0001; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0002; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0003; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0004; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0005; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0006; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0007; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0008; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0009; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Micro-dilution method assay
• Mechanism Description: Recombinant AAC(6')-Iag protein showed aminoglycoside 6'-N-acetyltransferase activity using thin-layer chromatography (TLC) and MS spectrometric analysis. Escherichia coli carrying aac(6')-Iag showed resistance to amikacin, arbekacin, dibekacin, isepamicin, kanamycin, sisomicin, and tobramycin; but not to gentamicin.AAC(6')-Iag is a functional acetyltransferase that modifies alternate amino groups on the AGs.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Putative ABC transporter ATP-binding component (OTRC) [28]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli ET12567 (pUZ8002); 562
• In Vitro Model: Streptomyces rimosus M4018; 1927
• In Vitro Model: Streptomyces rimosus SR16; 1927
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: OtrC is a multidrug resistance protein based on an ATP hydrolysis-dependent active efflux mechanism.OtrC is a multidrug resistance protein based on an ATP hydrolysis-dependent active efflux mechanism.

Doxycycline

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ARE-ABC-F family resistance factor PoxtA (POXTA) [64]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxycycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Escherichia coli Mach1 T1R; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth dilution test assay
• Mechanism Description: The poxtA gene encodes a protein that is 32% identical to OptrA and exhibits structural features typical of the F lineage of the ATP-binding cassette (ABC) protein superfamily that cause antibiotic resistance by ribosomal protection.

Enoxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83L
• Resistant Drug: Enoxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-112; 562
• In Vitro Model: Escherichia coli strain N-118; 562
• In Vitro Model: Escherichia coli strain N-119; 562
• In Vitro Model: Escherichia coli strain N-51; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83W
• Resistant Drug: Enoxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-18; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D87N
• Resistant Drug: Enoxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-113; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.G81C
• Resistant Drug: Enoxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-97; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A84P
• Resistant Drug: Enoxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-5; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A67S
• Resistant Drug: Enoxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-10; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Q106H
• Resistant Drug: Enoxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-89; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Ertapenem

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [44]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V88L+p.M154L
• Resistant Drug: Ertapenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli ST648; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: NDM-5 differed from existing enzymes due to substitutions at positions 88 (Val - Leu) and 154 (Met - Leu) and reduced the susceptibility of Escherichia coli TOP10 transformants to expanded-spectrum cephalosporins and carbapenems when expressed under its native promoter.

Erythromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase ermE (ERME) [79], [80], [81]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli AS19-RrmA-; 562
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli JC7623; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Methylation of specific nucleotides in rRNA is one of the means by which bacteria achieve resistance to macrolides-lincosamides-streptogramin B (MLSB) and ketolide antibiotics.ErmE dimethylation confers high resistance to all the MLSB and ketolide drugs.

Key Molecule: 23S ribosomal RNA methyltransferase Erm36 (ERM36) [87]

• Resistant Disease: Micrococcus luteus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Micrococcus luteus MAW843; 1270
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar diffusion test assay
• Mechanism Description: Erm(36) was most related (about 52-54% identity) to erythromycin-resistance proteins found in high-G+C Gram-positive bacteria and lead to drug resistance.

Key Molecule: erm(X)cj (Unclear) [82]

• Resistant Disease: Corynebacterium jeikeium infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Frameshift mutation; Codon 216 frame shift
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Corynebacterium diphtheriae isolate; 1717
• In Vitro Model: Corynebacterium glutamicum kO8; 1718
• In Vitro Model: Corynebacterium jeikeium isolates; 38289
• In Vitro Model: Escherichia coli ATCC 25923; 562
• In Vitro Model: Escherichia coli strain XL1-Blue MRF9; 562
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion methods assay; agar dilution methods assay
• Mechanism Description: Abundant amplificationproducts of slightly less than 400 bp were generated from DNAisolated from the 17 MLSb-resistant strains, whereas no am-plification products were generated with the DNA isolatedfrom the three susceptible strains. The DNA sequences of the amplification products showed 95% identity to the erm(X) gene isolated from a C. xerosis strain,erm(X)cx or ermCX. Thus, MLSb resistance in C. jeikeiumis associated with the presence of an allele, erm(X)cj, of the class Xermgenes. The first 215 amino acids of the predicted polypeptides for strains CJ12 and CJ21 are 93.5 and 98.6% identical to Erm(X)cx, the Erm protein from C. xerosi. The major difference between the two Erm(X)cj polypeptides and the Erm(X)cx polypeptide is a frame shift within codon 216. This results in the Erm(X)cj polypeptides being 31 amino acids longer than Erm(X)cx.

Key Molecule: Macrolide-lincosamide-streptogramin B resistance protein (ERMQ) [101]

• Resistant Disease: Clostridium perfringens infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Clostridium perfringens isolates; 1502
• In Vitro Model: Escherichia coli strain JM105; 83333
• In Vitro Model: Three MLS-resistant isolates of Clostridium difficile; 1496
• Experiment for Molecule Alteration: Pharmacia T7 Sequencing kits assay
• Mechanism Description: Erythromycin resistance among streptococci is commonly due to target site modification by an rRNA-methylating enzyme, which results in coresistance to macrolide, lincosamide, and streptogramin B antibiotics (MLSB resistance). An open reading frame with sequence similarity to erm genes from other bacteria was identified and designated the ermQ gene. On the basis of comparative sequence analysis, it was concluded that the ermQ gene represented a new Erm hybridization class, designated ErmQ. The ermQ gene therefore represents the most common erythromycin resistance determinant in C. perfringens.

Key Molecule: rRNA adenine N-6-methyltransferase ermC' (ERMC) [102], [103], [104]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bacillus subtilis strain BD170; 1423
• In Vitro Model: Bacillus subtilis strain BD430; 1423
• In Vitro Model: Bacillus subtilis strain BD431; 1423
• In Vitro Model: Bacillus subtilis strain BD488; 1423
• In Vitro Model: Bacillus subtilis strain BD81; 1423
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The ermC gene of plasmid pE194 specifies resistance to the macrolidelincosamide-streptogramin B antibiotics. pE194 specifies an RNA methylase that can utilize either 50 S ribosomes or 23 S rRNA as substrates,with a specific dimethylation of adenine in 23 S rRNA.

Key Molecule: ErmR rRNA adenine N6-methyltransferase (ERMR) [88]

• Resistant Disease: Aeromicrobium erythreum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Erythromycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Aeromicrobium erythreum strains AR18; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1807; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1848; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1849; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1850; 2041
• In Vitro Model: Aeromicrobium erythreum strains BD170; 2041
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: Using the Ery- strain AR1807 as a recipient for plasmid-directed integrative recombination, the chromosomal ermR gene (encoding 23S rRNA methyltransferase) was disrupted, ermR-disrupted strains AR1848 and AR1849 were highly sensitive to erythromycin and the other macrolide antibiotics. Phenotypic characterizations demonstrated that ermR is the sole determinant of macrolide antibiotic resistance in A. erythreum. AR18, AR1807, and AR1850 (Ery- Ermr) were resistant to clindamycin, erythromycin, spiramycin, and tylosin (some sensitivity totylosin was observed at high concentrations).

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Macrolide 2'-phosphotransferase II (MPHB) [105], [106], [107]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AG100A; 562
• In Vitro Model: Escherichia coli DB10; 562
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli XL1-Blue; 562
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Mph enzymes inactivate macrolides by phosphorylating the 2'-OH of the essential dimethylamino sugar, preventing it from binding the ribosome, and providing the chemical rationale for the resistance phenotype.

Key Molecule: Oleandomycin glycosyltransferase oleD (OLED) [108], [109], [110]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli GT-28; 562
• In Vitro Model: Escherichia coli MurG; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: OleD displays broad acceptor specificity and hence will inactivate a wider range of macrolide antibiotics including tylosin and erythromycin.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter ATPase subunit (ABCS) [25], [26], [27]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis isolates; 1351
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Multidrug efflux pump extraction, purification, and sequencing showed the distribution of mefA and msrA/msrB efflux pumps.

Key Molecule: Major facilitator superfamily efflux pump (AMVA) [111]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Acinetobacter baumannii AC0037; 470
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Molecular and functional characterization of a novel efflux pump, AmvA, mediating antimicrobial and disinfectant resistance in Acinetobacter baumannii.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ErmR rRNA adenine N6-methyltransferase (ERMR) [88]

• Sensitive Disease: Aeromicrobium erythreum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Chromosome variation; Chromosome rearrangement
• Sensitive Drug: Erythromycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Aeromicrobium erythreum strains AR18; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1807; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1848; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1849; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1850; 2041
• In Vitro Model: Aeromicrobium erythreum strains BD170; 2041
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: Using the Ery- strain AR1807 as a recipient for plasmid-directed integrative recombination, the chromosomal ermR gene (encoding 23S rRNA methyltransferase) was disrupted, ermR-disrupted strains AR1848 and AR1849 were highly sensitive to erythromycin and the other macrolide antibiotics. Phenotypic characterizations demonstrated that ermR is the sole determinant of macrolide antibiotic resistance in A. erythreum.

Fidaxomicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA-directed RNA polymerase subunit beta' (RPOC) [112]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D244Y
• Resistant Drug: Fidaxomicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Clostridioides difficile ATCC 43255; 499175
• In Vitro Model: Clostridioides difficile NB95009; 1496
• In Vitro Model: Clostridioides difficile NB95026; 1496
• In Vitro Model: Clostridioides difficile NB95031; 1496
• In Vitro Model: Clostridioides difficile NB95047; 1496
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: NB95026-JAL0865 had a single mutation encoding a D244Y substitution in the RNA polymerase subunit Beta.Reduced susceptibility to fidaxomicin and vancomycin was associated with mutations mediating target modifications (RNA polymerase and cell wall, respectively), as well as with mutations that may contribute to reduced susceptibility via other mechanisms.

Florfenicol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Carboxymethylenebutenolidase (CLCD) [84]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Florfenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli AS19; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The Cfr RNA methyltransferase causes multiple resistances to peptidyl transferase inhibitors by methylation of A2503 23S rRNA.clcD codes the same enzyme.

Key Molecule: Ribosomal RNA large subunit methyltransferase (CFR ) [85]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Florfenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Cfr confers resistance to antibiotics binding to the peptidyl transferase center on the ribosome.The primary product of the Cfr-mediated methylation is 8-methyladenosine (m8A), a new natural RNA modification that has so far not been seen at sites other than A2503 in 23S rRNA.

Key Molecule: 23S rRNA (Adenine(2503)-C(8))-methyltransferase ClbA (CIBA) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Florfenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ARE-ABC-F family resistance factor PoxtA (POXTA) [64]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Florfenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Escherichia coli Mach1 T1R; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth dilution test assay
• Mechanism Description: The poxtA gene encodes a protein that is 32% identical to OptrA and exhibits structural features typical of the F lineage of the ATP-binding cassette (ABC) protein superfamily that cause antibiotic resistance by ribosomal protection.

Key Molecule: Protein pexA (PEXA) [65]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Florfenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• Experiment for Molecule Alteration: Nucleotide sequence assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: In its natural host, pexA could provide protection against chloramphenicol and florfenicol excreted by Streptomyces spp.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Colibactin polyketide synthase ClbC (CLBC) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Florfenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Fluoroquinolones

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Fluoroquinolone efflux MFS transporter QepA1 (QEPA1) [113]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Fluoroquinolones
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C316; 562
• Experiment for Molecule Alteration: DNA sequencing and alignment assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: QepA is a new quinolone efflux pump protein responsible for fluoroquinolone resistance.

Key Molecule: Multidrug resistance protein PmpM (PMPM) [1]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Fluoroquinolones
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32/pSTV28; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: PmpM is a multi drug efflux pump coupled with hydrogen ions, which reduces the intracellular drug concentration and produces drug resistance.

Framycetin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 16S rRNA (adenine(1408)-N(1))-methyltransferase (KAMB) [114], [115]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Framycetin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The 16S ribosomal RNA methyltransferase enzymes that modify nucleosides in the drug binding site to provide self-resistance in aminoglycoside-producing micro-organisms have been proposed to comprise two distinct groups of S-adenosyl-l-methionine (SAM)-dependent RNA enzymes, namely the kgm and kam families.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [116]

• Resistant Disease: Stenotrophomonas maltophilia infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Framycetin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• Experiment for Molecule Alteration: PCR amplification assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Aph(3')-IIc significantly increases MICs of kanamycin, neomycin, butirosin, and paromomycin when expressed in Escherichia coli. Disruption of aph(3')-IIc results in decreased MICs of these drugs.

Key Molecule: Aminoglycoside N(3)-acetyltransferase VIII (A3AC8) [117]

• Resistant Disease: Micromonospora chalcea infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Framycetin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Micromonospora chalcea strain 69-683; 1874
• In Vitro Model: Streptomyces fradiae strain ATCC 10745; 1319510
• Experiment for Molecule Alteration: Southern-blot hybridization assay
• Mechanism Description: In the case of S. fradiae ATCC10745, a Nm producer, an O-phosphotransferase (APH) encoded by the aphA-5 gene and an N-acetyltransferase (AAC) have been identified. The aphA-5 gene is thought to be part of a biosynthetic cluster; the sac gene is not closely linked to aph; however, high-level Nm resistance in Streptomyces requires expression of both uph and sac. Nm production has been found also in the genus Mcromonospora, especially in M. chalcea 69-683, which possesses both APH and AAC activities. Little is known of Mcromonospora molecular biology, and with a view to comparing the two Nm producers and their resistance mechanisms, we have cloned, expressed and characterised the two resistance determinants from M. chalcea and from S. frudiue.

Key Molecule: Aminoglycoside N(3)-acetyltransferase IX (A3AC9) [117]

• Resistant Disease: Micromonospora chalcea infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Framycetin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Micromonospora chalcea strain 69-683; 1874
• In Vitro Model: Streptomyces fradiae strain ATCC 10745; 1319510
• Experiment for Molecule Alteration: Southern-blot hybridization assay
• Mechanism Description: In the case of S. fradiae ATCC10745, a Nm producer, an O-phosphotransferase (APH) encoded by the aphA-5 gene and an N-acetyltransferase (AAC) have been identified. The aphA-5 gene is thought to be part of a biosynthetic cluster; the sac gene is not closely linked to aph; however, high-level Nm resistance in Streptomyces requires expression of both uph and sac. Nm production has been found also in the genus Mcromonospora, especially in M. chalcea 69-683, which possesses both APH and AAC activities. Little is known of Mcromonospora molecular biology, and with a view to comparing the two Nm producers and their resistance mechanisms, we have cloned, expressed and characterised the two resistance determinants from M. chalcea and from S. frudiue.

Furazolidone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside acetyltransferase (AAC) [22]

• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Furazolidone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Gentamicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [2]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Intergeneric lateral gene transfer
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa AR-2; 287
• Experiment for Molecule Alteration: PCR screening assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The 16S rRNA methylase gene has undergone intergeneric horizontal gene transfer from some aminoglycoside producing microorganisms to Pseudomonas aeruginosa, which is called rmtA. rmtA protect bacterial 16S rRNA from intrinsic aminoglycosides by methylation.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (AACC2) [118], [9]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Staphylococcus aureus ATCC 25923; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Various aminoglycoside modifying enzymes were associated with overlapping phenotypes: 36.5% strains produced AAC(6')-I with either a serine (GEN-TOB-NET) or a leucine (TOB-NET-AMk) at position 119, or both variants (GEN-TOB-NET-AMk); 21.2% expressed ANT(2")-I (GEN-TOB), 7.7% AAC(3)-II (GEN-TOB-NET), 5.8% AAC(3)-I (GEN) and 1.9% AAC(6')-II (GEN-TOB-NET-AMk) or AACA7 (TOB-NET-AMk).

Key Molecule: Aminoglycoside acetyltransferase (AAC) [22]

• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [4]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• Experiment for Molecule Alteration: PCR mapping and sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Aac(3)-Ic gene could contribute to aminoglycoside resistance with a pattern typical of AAC(3)-I enzymes.

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

Key Molecule: Aminoglycoside N(3)-acetyltransferase (A3AC) [119], [120]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Enterobacter cloacae strain 88020217; 550
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The resistance profile conferred by the AAC(3)-VIa enzyme,which encodes this novel 3-N-acetyltransferase,includes high-level resistance to gentamicin,sisomicin, and 6'-N-ethylnetilmicin and moderate levels of resistance to tobramycin and netilmicin.

Key Molecule: AADA2 protein (AADA2) [121], [122]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM83; 562
• In Vitro Model: Escherichia coli strain k802N; 562
• In Vitro Model: Pseudomonas aeruginosa strain BM2692; 287
• In Vitro Model: Pseudomonas aeruginosa strain BM2693; 287
• In Vitro Model: Pseudomonas aeruginosa strain BM2694; 287
• In Vitro Model: Pseudomonas aeruginosa strain BM2695; 287
• In Vitro Model: Pseudomonas fluorescens strain BM2687; 294
• In Vitro Model: Pseudomonas fluorescens strain BM2687-1; 294
• In Vitro Model: Pseudomonas fluorescens strain BM2687-2; 294
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: The aac(6')-Ib' gene from Pseudomonas fluorescens BM2687, encoding an aminoglycoside 6'-N-acetyltransferase type II which confers resistance to gentamicin but not to amikacin, was characterized.

Key Molecule: Aminoglycoside N(3)-acetyltransferase III (A3AC3) [8], [9]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Serratia marcescens strain 82041944; 615
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The AAC(3)-V resistance mechanism is characterized by high-level resistance to the aminoglycosides gentamicin, netilmicin, 2'-N-ethylnetilmicin, and 6'-N-ethylnetilmicin and moderate resistance levels to tobramycin.

Gentamicin B

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [123]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Methylation; p.M7G1405
• Resistant Drug: Gentamicin B
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• Experiment for Molecule Alteration: Protein-RNA footprinting assay
• Experiment for Drug Resistance: Isothermal titration calorimetry assay
• Mechanism Description: Sgm methylates G1405 in 16S rRNA to m7G, thereby rendering the ribosome resistant to 4, 6-disubstituted deoxystreptamine aminoglycosides.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (AACC2) [9], [124], [125]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gentamicin B
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Pseudomonas aeruginosa PAe1100; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The AAC(3)-II AGRP is characterized by resistance to gentamicin, tobramycin, dibekacin, netilmicin, 2'-N-ethylnetilmicin, 6'-N-ethylnetilmicin, and sisomicin.

Key Molecule: Aminoglycoside adenyltransferase 2''-Ia (ANT2I) [126], [127]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gentamicin B
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AB5075; 1116234
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: ANT(2")-Ia confers resistance by magnesium-dependent transfer of a nucleoside monophosphate (AMP) to the 2"-hydroxyl of aminoglycoside substrates containing a 2-deoxystreptamine core.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [7]

• Resistant Disease: Serratia marcescens infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin B
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Key Molecule: Gentamicin 3'-acetyltransferase (AACC1) [128], [129]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gentamicin B
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain BN; 562
• In Vitro Model: Escherichia coli strain J62; 562
• In Vitro Model: Escherichia coli strain k12 W3110; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: The most common mechanisms of resistance to aminoglycoside-aminocyclitol (AG) antibiotics in bacteria are exerted by enzymatic modification which results in failure of their binding to ribosomal targets and in prevention of uptake by the cell.

Gentamicin C

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [123]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Methylation; p.M7G1405
• Resistant Drug: Gentamicin C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• Experiment for Molecule Alteration: Protein-RNA footprinting assay
• Experiment for Drug Resistance: Isothermal titration calorimetry assay
• Mechanism Description: Sgm methylates G1405 in 16S rRNA to m7G, thereby rendering the ribosome resistant to 4, 6-disubstituted deoxystreptamine aminoglycosides.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (AACC2) [9], [124], [125]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gentamicin C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Pseudomonas aeruginosa PAe1100; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The AAC(3)-II AGRP is characterized by resistance to gentamicin, tobramycin, dibekacin, netilmicin, 2'-N-ethylnetilmicin, 6'-N-ethylnetilmicin, and sisomicin.

Key Molecule: Aminoglycoside adenyltransferase 2''-Ia (ANT2I) [126], [127]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gentamicin C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AB5075; 1116234
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: ANT(2")-Ia confers resistance by magnesium-dependent transfer of a nucleoside monophosphate (AMP) to the 2"-hydroxyl of aminoglycoside substrates containing a 2-deoxystreptamine core.

Key Molecule: AAC(6')-Ib family aminoglycoside 6'-N-acetyltransferase (AAC6IB) [130]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Escherichia coli k-12; 83333
• In Vitro Model: Pseudomonas aeruginosa Pa695; 287
• Experiment for Molecule Alteration: PCR experiments assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: The fusion product was functional, as was the product of each gene cloned separately: AAC(3)-I, despite the deletion of the four last amino acids, and AAC(6"), which carried three amino acid changes compared with the most homologous sequence. The AAC(3)-I protein conferred an expected gentamicin and fortimicin resistance, and the AAC(6"), despite the Leu-119-Ser substitution, yielded resistance to kanamycin, tobramycin, and dibekacin, but slightly affected netilmicin and amikacin, and had no apparent effect on gentamicin. The fusion product conveyed a large profile of resistance, combining the AAC(6") activity with a higher level of gentamicin resistance without accompanying fortimicin resistance.

Key Molecule: Gentamicin 3'-acetyltransferase (AACC1) [128], [129]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gentamicin C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain BN; 562
• In Vitro Model: Escherichia coli strain J62; 562
• In Vitro Model: Escherichia coli strain k12 W3110; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: The most common mechanisms of resistance to aminoglycoside-aminocyclitol (AG) antibiotics in bacteria are exerted by enzymatic modification which results in failure of their binding to ribosomal targets and in prevention of uptake by the cell.

Isepamicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [2]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Intergeneric lateral gene transfer
• Resistant Drug: Isepamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa AR-2; 287
• Experiment for Molecule Alteration: PCR screening assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The 16S rRNA methylase gene has undergone intergeneric horizontal gene transfer from some aminoglycoside producing microorganisms to Pseudomonas aeruginosa, which is called rmtA. rmtA protect bacterial 16S rRNA from intrinsic aminoglycosides by methylation.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(6')-acetyltransferase type 1 (A6AC1) [3]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Isepamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa Nk0001; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0002; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0003; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0004; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0005; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0006; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0007; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0008; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0009; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Micro-dilution method assay
• Mechanism Description: Recombinant AAC(6')-Iag protein showed aminoglycoside 6'-N-acetyltransferase activity using thin-layer chromatography (TLC) and MS spectrometric analysis. Escherichia coli carrying aac(6')-Iag showed resistance to amikacin, arbekacin, dibekacin, isepamicin, kanamycin, sisomicin, and tobramycin; but not to gentamicin.AAC(6')-Iag is a functional acetyltransferase that modifies alternate amino groups on the AGs.

Kanamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA methyltransferase PikR1 (PIKR1) [131], [132]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Kanamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli BL21(DE3)pLysS; 866768
• In Vitro Model: Escherichia coli S17-1; 1227813
• In Vitro Model: Streptomyces antibioticus ATCC 11891; 1890
• In Vitro Model: Streptomyces venezuelae ATCC 15439; 54571
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Modification of 23S rRNA, which is the target site for methymycin and its derivatives, by PikR1 and PikR2 is a primary self-resistance mechanism.

Key Molecule: rRNA methyltransferase PikR2 (PIKR2) [131], [132]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Kanamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli BL21(DE3)pLysS; 866768
• In Vitro Model: Escherichia coli S17-1; 1227813
• In Vitro Model: Streptomyces antibioticus ATCC 11891; 1890
• In Vitro Model: Streptomyces venezuelae ATCC 15439; 54571
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Modification of 23S rRNA, which is the target site for methymycin and its derivatives, by PikR1 and PikR2 is a primary self-resistance mechanism.

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [123]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Methylation; p.M7G1405
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• Experiment for Molecule Alteration: Protein-RNA footprinting assay
• Experiment for Drug Resistance: Isothermal titration calorimetry assay
• Mechanism Description: Sgm methylates G1405 in 16S rRNA to m7G, thereby rendering the ribosome resistant to 4, 6-disubstituted deoxystreptamine aminoglycosides.

Key Molecule: 16S rRNA (adenine(1408)-N(1))-methyltransferase (KAMB) [114], [115]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The 16S ribosomal RNA methyltransferase enzymes that modify nucleosides in the drug binding site to provide self-resistance in aminoglycoside-producing micro-organisms have been proposed to comprise two distinct groups of S-adenosyl-l-methionine (SAM)-dependent RNA enzymes, namely the kgm and kam families.

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [2]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Intergeneric lateral gene transfer
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa AR-2; 287
• Experiment for Molecule Alteration: PCR screening assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The 16S rRNA methylase gene has undergone intergeneric horizontal gene transfer from some aminoglycoside producing microorganisms to Pseudomonas aeruginosa, which is called rmtA. rmtA protect bacterial 16S rRNA from intrinsic aminoglycosides by methylation.

Key Molecule: erm(X)cj (Unclear) [82]

• Resistant Disease: Corynebacterium jeikeium infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Frameshift mutation; Codon 216 frame shift
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Corynebacterium diphtheriae isolate; 1717
• In Vitro Model: Corynebacterium glutamicum kO8; 1718
• In Vitro Model: Corynebacterium jeikeium isolates; 38289
• In Vitro Model: Escherichia coli ATCC 25923; 562
• In Vitro Model: Escherichia coli strain XL1-Blue MRF9; 562
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion methods assay; agar dilution methods assay
• Mechanism Description: Abundant amplificationproducts of slightly less than 400 bp were generated from DNAisolated from the 17 MLSb-resistant strains, whereas no am-plification products were generated with the DNA isolatedfrom the three susceptible strains. The DNA sequences of the amplification products showed 95% identity to the erm(X) gene isolated from a C. xerosis strain,erm(X)cx or ermCX. Thus, MLSb resistance in C. jeikeiumis associated with the presence of an allele, erm(X)cj, of the class Xermgenes. The first 215 amino acids of the predicted polypeptides for strains CJ12 and CJ21 are 93.5 and 98.6% identical to Erm(X)cx, the Erm protein from C. xerosi. The major difference between the two Erm(X)cj polypeptides and the Erm(X)cx polypeptide is a frame shift within codon 216. This results in the Erm(X)cj polypeptides being 31 amino acids longer than Erm(X)cx.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: AacA43 aminoglycoside (AACA43) [133]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Klebsiella pneumoniae LT12; 573
• In Vitro Model: Klebsiella pneumoniae SSI2.46; 573
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Like related aminoglycoside-(6')-acetyltransferases, AacA43 confers clinically relevant resistance to kanamycin, tobramycin, and some less-used aminoglycosides but not to gentamicin.

Key Molecule: Aminoglycoside N(6')-acetyltransferase type 1 (A6AC1) [3]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa Nk0001; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0002; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0003; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0004; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0005; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0006; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0007; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0008; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0009; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Micro-dilution method assay
• Mechanism Description: Recombinant AAC(6')-Iag protein showed aminoglycoside 6'-N-acetyltransferase activity using thin-layer chromatography (TLC) and MS spectrometric analysis. Escherichia coli carrying aac(6')-Iag showed resistance to amikacin, arbekacin, dibekacin, isepamicin, kanamycin, sisomicin, and tobramycin; but not to gentamicin.AAC(6')-Iag is a functional acetyltransferase that modifies alternate amino groups on the AGs.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [116]

• Resistant Disease: Stenotrophomonas maltophilia infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• Experiment for Molecule Alteration: PCR amplification assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Aph(3')-IIc significantly increases MICs of kanamycin, neomycin, butirosin, and paromomycin when expressed in Escherichia coli. Disruption of aph(3')-IIc results in decreased MICs of these drugs.

Key Molecule: AAC(6')-Ib family aminoglycoside 6'-N-acetyltransferase (AAC6IB) [130]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Escherichia coli k-12; 83333
• In Vitro Model: Pseudomonas aeruginosa Pa695; 287
• Experiment for Molecule Alteration: PCR experiments assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: The fusion product was functional, as was the product of each gene cloned separately: AAC(3)-I, despite the deletion of the four last amino acids, and AAC(6"), which carried three amino acid changes compared with the most homologous sequence. The AAC(3)-I protein conferred an expected gentamicin and fortimicin resistance, and the AAC(6"), despite the Leu-119-Ser substitution, yielded resistance to kanamycin, tobramycin, and dibekacin, but slightly affected netilmicin and amikacin, and had no apparent effect on gentamicin. The fusion product conveyed a large profile of resistance, combining the AAC(6") activity with a higher level of gentamicin resistance without accompanying fortimicin resistance.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [6]

• Resistant Disease: Streptococcus faecalis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Kanamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain JM 10; 562
• In Vitro Model: Escherichia coli strain k802; 562
• In Vitro Model: Streptococcus faecnlis strain JHZ-15; 1351
• Experiment for Molecule Alteration: Chemical sequencing method assay
• Experiment for Drug Resistance: Disc sensitivity tests assay
• Mechanism Description: Streptococcus jaecalis strain JH2- 15 is resistant to high levels of kanamycin (MIC > 1 mg/ml) and structurally related antibiotics. This broad-resistance phenotype is due to the presence of an APH-III. The gene encoding the enzyme in JH2-15 is borne by a 72.6-kb R plasmid, pJH1, capable of self-transfer to streptococcal cells. In pathogenic bacteria, 3'-aminoglycoside phosphotransferases exist under three (types I, II, and III) isozymic forms which differ, in particular, in their substrate ranges. APH-III enzyme appears to be specific for the Gram-positive cocci, whereas 3'-phosphotransferases of types I and II are found exclusively in Gram-negative bacteria.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [7]

• Resistant Disease: Serratia marcescens infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Kasugamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Kasugamycin 2' acetyltransferase (KA2A) [35]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Kasugamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Paenibacillus sp. LC231; 1120679
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside acetyltransferases can often modify a variety of aminoglycosides and we therefore evaluated the ability of AAC(2')-IIb to modify a range of aminoglycosides. AAC(2')-IIb specifically modified kasugamycin and no other aminoglycoside by acetylation.

Levofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA gyrase subunit A (GYRA) [73]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83L; p.S80L
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• Experiment for Molecule Alteration: ERIC-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Mutations that occur in gyrA and parC genes were detected by DNA sequence analysis in 16 resistant strains representing each clone and subtype.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [73]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83L; p.S80L
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• Experiment for Molecule Alteration: ERIC-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Mutations that occur in gyrA and parC genes were detected by DNA sequence analysis in 16 resistant strains representing each clone and subtype.

Key Molecule: DNA gyrase subunit A (GYRA) [134], [135]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T83I
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Burkholderia cepacia isolates; 292
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Among six levofloxacin-resistant isolates, five had single-base substitutions in the gyrA gene.

Key Molecule: DNA gyrase subunit A (GYRA) [134], [135]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D87H
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Burkholderia cepacia isolates; 292
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Among six levofloxacin-resistant isolates, five had single-base substitutions in the gyrA gene.

Key Molecule: DNA gyrase subunit A (GYRA) [134], [135]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.G81D
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Burkholderia cepacia isolates; 292
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Among six levofloxacin-resistant isolates, five had single-base substitutions in the gyrA gene.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [74]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S463A
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [74]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S464Y
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [74]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S80I
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Lincomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase ermE (ERME) [79], [80], [81]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Lincomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli AS19-RrmA-; 562
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli JC7623; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Methylation of specific nucleotides in rRNA is one of the means by which bacteria achieve resistance to macrolides-lincosamides-streptogramin B (MLSB) and ketolide antibiotics.ErmE dimethylation confers high resistance to all the MLSB and ketolide drugs.

Key Molecule: 23S ribosomal RNA methyltransferase Erm36 (ERM36) [87]

• Resistant Disease: Micrococcus luteus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Lincomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Micrococcus luteus MAW843; 1270
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar diffusion test assay
• Mechanism Description: Erm(36) was most related (about 52-54% identity) to erythromycin-resistance proteins found in high-G+C Gram-positive bacteria and lead to drug resistance.

Key Molecule: erm(X)cj (Unclear) [82]

• Resistant Disease: Corynebacterium jeikeium infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Frameshift mutation; Codon 216 frame shift
• Resistant Drug: Lincomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Corynebacterium diphtheriae isolate; 1717
• In Vitro Model: Corynebacterium glutamicum kO8; 1718
• In Vitro Model: Corynebacterium jeikeium isolates; 38289
• In Vitro Model: Escherichia coli ATCC 25923; 562
• In Vitro Model: Escherichia coli strain XL1-Blue MRF9; 562
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion methods assay; agar dilution methods assay
• Mechanism Description: Abundant amplificationproducts of slightly less than 400 bp were generated from DNAisolated from the 17 MLSb-resistant strains, whereas no am-plification products were generated with the DNA isolatedfrom the three susceptible strains. The DNA sequences of the amplification products showed 95% identity to the erm(X) gene isolated from a C. xerosis strain,erm(X)cx or ermCX. Thus, MLSb resistance in C. jeikeiumis associated with the presence of an allele, erm(X)cj, of the class Xermgenes. The first 215 amino acids of the predicted polypeptides for strains CJ12 and CJ21 are 93.5 and 98.6% identical to Erm(X)cx, the Erm protein from C. xerosi. The major difference between the two Erm(X)cj polypeptides and the Erm(X)cx polypeptide is a frame shift within codon 216. This results in the Erm(X)cj polypeptides being 31 amino acids longer than Erm(X)cx.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Lincosamide nucleotidyltransferase (LNUG) [136]

• Resistant Disease: Enterococcus faecalis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Lincomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Enterococcus faecalis; 1351
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Mechanism Description: A novel resistance gene, designated lnu(G), which encodes a putative lincosamide nucleotidyltransferase, was found in E. faecalis E531.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC superfamily ATP binding cassette transporter (ABCCT) [137], [138]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Lincomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• In Vitro Model: Staphylococcus saprophyticus ATCC 15305; 342451
• In Vitro Model: Staphylococcus sciuri ATCC 29059; 1296
• In Vitro Model: Staphylococcus sciuri ATCC 29062; 1296
• In Vitro Model: Staphylococcus sciuri ATCC 700058; 1296
• In Vitro Model: Staphylococcus sciuri ATCC 700061; 1296
• In Vitro Model: Staphylococcus sciuri BL2; 1296
• In Vitro Model: Staphylococcus sciuri SS226; 1296
• In Vitro Model: Staphylococcus sciuri SVv1; 1296
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: Efflux-mediated resistance to MLS antibiotics in staphylococci relies on the ATPase activity of a very special kind of ATP-binding cassette (ABC) protein.By whole-genome sequencing of strain ATCC 29059, we identified a candidate gene that encodes an ATP-binding cassette protein similar to the Lsa and VmlR resistance determinants. Isolation and reverse transcription-quantitative PCR (qRT-PCR) expression studies confirmed that Sal(A) can confer a moderate resistance to lincosamides (8 times the MIC of lincomycin) and a high-level resistance to streptogramins A. The chromosomal location of sal(A) between two housekeeping genes of the staphylococcal core genome supports the gene's ancient origins and thus innate resistance to these antimicrobials within S. sciuri subspecies.

Key Molecule: ABC transporter ATP-binding protein (ABCP) [89], [90]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T450I
• Resistant Drug: Lincomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Enterococcus faecium HM1070; 1352
• In Vitro Model: Enterococcus faecium UCN80; 1352
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: ABC systems constitute one of the largest families of proteins, with most of them being involved in import and export, often called ABC transporters.Several of these class 2 ABC systems have been involved in MLS resistance, such as Msr-, Vga-, or Lsa-like proteins.The observed profile of cross-resistance to lincosamides, streptogramins A, and pleuromutilins conferred by Eat(A)v was similar to those conferred by other Lsa-like proteins.

Linezolid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Carboxymethylenebutenolidase (CLCD) [84]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Linezolid
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli AS19; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The Cfr RNA methyltransferase causes multiple resistances to peptidyl transferase inhibitors by methylation of A2503 23S rRNA.clcD codes the same enzyme.

Key Molecule: Ribosomal RNA large subunit methyltransferase (CFR ) [85]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Linezolid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Cfr confers resistance to antibiotics binding to the peptidyl transferase center on the ribosome.The primary product of the Cfr-mediated methylation is 8-methyladenosine (m8A), a new natural RNA modification that has so far not been seen at sites other than A2503 in 23S rRNA.

Key Molecule: 23S rRNA (Adenine(2503)-C(8))-methyltransferase ClbA (CIBA) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Linezolid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ARE-ABC-F family resistance factor PoxtA (POXTA) [64]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Linezolid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Escherichia coli Mach1 T1R; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth dilution test assay
• Mechanism Description: The poxtA gene encodes a protein that is 32% identical to OptrA and exhibits structural features typical of the F lineage of the ATP-binding cassette (ABC) protein superfamily that cause antibiotic resistance by ribosomal protection.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Colibactin polyketide synthase ClbC (CLBC) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Linezolid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Macrolides

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase ermC' (ERMC) [102], [103], [104]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Macrolides
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bacillus subtilis strain BD170; 1423
• In Vitro Model: Bacillus subtilis strain BD430; 1423
• In Vitro Model: Bacillus subtilis strain BD431; 1423
• In Vitro Model: Bacillus subtilis strain BD488; 1423
• In Vitro Model: Bacillus subtilis strain BD81; 1423
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The ermC gene of plasmid pE194 specifies resistance to the macrolidelincosamide-streptogramin B antibiotics. pE194 specifies an RNA methylase that can utilize either 50 S ribosomes or 23 S rRNA as substrates,with a specific dimethylation of adenine in 23 S rRNA.

Key Molecule: ErmR rRNA adenine N6-methyltransferase (ERMR) [88]

• Resistant Disease: Aeromicrobium erythreum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Macrolides
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Aeromicrobium erythreum strains AR18; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1807; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1848; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1849; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1850; 2041
• In Vitro Model: Aeromicrobium erythreum strains BD170; 2041
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: Using the Ery- strain AR1807 as a recipient for plasmid-directed integrative recombination, the chromosomal ermR gene (encoding 23S rRNA methyltransferase) was disrupted, ermR-disrupted strains AR1848 and AR1849 were highly sensitive to erythromycin and the other macrolide antibiotics. Phenotypic characterizations demonstrated that ermR is the sole determinant of macrolide antibiotic resistance in A. erythreum. AR18, AR1807, and AR1850 (Ery- Ermr) were resistant to clindamycin, erythromycin, spiramycin, and tylosin (some sensitivity totylosin was observed at high concentrations).

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Oleandomycin glycosyltransferase oleD (OLED) [108], [109], [110]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Macrolides
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli GT-28; 562
• In Vitro Model: Escherichia coli MurG; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: OleD displays broad acceptor specificity and hence will inactivate a wider range of macrolide antibiotics including tylosin and erythromycin.

Matromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S ribosomal RNA methyltransferase Erm36 (ERM36) [87]

• Resistant Disease: Micrococcus luteus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Matromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Micrococcus luteus MAW843; 1270
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar diffusion test assay
• Mechanism Description: Erm(36) was most related (about 52-54% identity) to erythromycin-resistance proteins found in high-G+C Gram-positive bacteria and lead to drug resistance.

Meropenem

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: CATB10-Ib variant (CATB10) [48]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Meropenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa TS-103; 287
• In Vitro Model: Pseudomonas aeruginosa TS-832035; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: P. aeruginosa TS-832035 produces a carbapenemase, coded by a blaVIM-1 determinant carried by the chromosomal class 1 integron In70.2 (containing also the aacA4, aphA15, and aadA1 genes in its cassette array),which induce the resistance to carbapenems.

Key Molecule: Metallo-beta-lactamase (VIM1) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Meropenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: A. xylosoxydans AX22 exhibited broad-spectrum resistance to Beta-lactams and aminoglycosides. The Beta-lactam resistance pattern (including piperacillin, ceftazidime, and carbapenem resistance) was unusual for this species, and the high-level carbapenem resistance suggested the production of an acquired carbapenemase. In fact, carbapenemase activity was detected in a crude extract of AX22 (specific activity, 184 +/- 12 U/mg of protein), and this activity was reduced (>80%) after incubation of the crude extract with 2 mM EDTA, suggesting the presence of a metallo-Beta-lactamase determinant.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: TolC family outer membrane protein (TOLC) [10]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Meropenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AYE WT; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO Omega abuO; 509173
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: AbuO, an OMP, confers broad-spectrum antimicrobial resistance via active efflux in A. baumannii.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Pyruvate decarboxylase 5 (PDC5) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• Resistant Drug: Meropenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Key Molecule: Pyruvate decarboxylase 3 (PDC3) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T97A
• Resistant Drug: Meropenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Meticillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Alternative penicillin-binding protein 2a (MECD) [139]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Meticillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Macrococcus caseolyticus strains; 69966
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Mechanism Description: Methicillin-resistant Macrococcus caseolyticus strains from bovine and canine origins were found to carry a novel mecD gene conferring resistance to all classes of Beta-lactams including anti-MRSA cephalosporins. Association of Beta-lactam resistance with mecD was demonstrated by gene expression in S. aureus and deletion of the mecD-containing island in M. caseolyticus.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [34]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Meticillin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM 160(Y); 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM158; 1063
• In Vitro Model: Rhodopseudomonas sphaeroides strain DSM159; 1063
• Experiment for Molecule Alteration: Sodium dodecyl sulfate-PAGE assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Thirteen strains of the gram-negative, facultative phototrophic bacterium Rhodobacter sphaeroides were examined fro susceptibility to beta-lactam antibiotics. All strains were sensitive to the semisynthetic penicillins ampicillin, carbenicillin, oxacillin, cloxacillin, and methicillin, but 10 of the 13 strains were resistant to penicillin G, as well as a number of cephalosporins, such as cephalothin, cephapirin, and cephalosporin C. A beta-lactamase (EC 3.5.2.6) with strong cephalosporinase activity was detected in all of the resistant strains of R. sphaeroides. With strain Y-1 as a model, it was shown that the beta-lactamase was inducible by penicillin G, cephalosporin C, cephalothin, and to some minor extent, cephapirin.

Mezlocillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase (VIM1) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Mezlocillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: A. xylosoxydans AX22 exhibited broad-spectrum resistance to Beta-lactams and aminoglycosides. The Beta-lactam resistance pattern (including piperacillin, ceftazidime, and carbapenem resistance) was unusual for this species, and the high-level carbapenem resistance suggested the production of an acquired carbapenemase. In fact, carbapenemase activity was detected in a crude extract of AX22 (specific activity, 184 +/- 12 U/mg of protein), and this activity was reduced (>80%) after incubation of the crude extract with 2 mM EDTA, suggesting the presence of a metallo-Beta-lactamase determinant.

Minocycline

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tetracycline resistance protein Tet (TETW/N/W) [70]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Minocycline
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli EPI-300; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Tet(W/N/W) encodes mosaic ribosomal protection(since tetracyclines bind to the 30S ribosomal subunit to inhibit protein translation) and induces resistance.

Key Molecule: Protein TetT (TETT) [140]

• Resistant Disease: Streptococcus pyogenes infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Minocycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain TG1; 562
• In Vitro Model: Streptococcus agalactiae strain B130; 1311
• In Vitro Model: Streptococcus anginosus strain MG16; 1328
• In Vitro Model: Streptococcus anginosus strain MG23; 1328
• In Vitro Model: Streptococcus anginosus strain MG32; 1328
• In Vitro Model: Streptococcus bovis strain D135; 1335
• In Vitro Model: Streptococcus bovis strain D295; 1335
• In Vitro Model: Streptococcus equisimilis strain C94; 119602
• In Vitro Model: Streptococcus equisimilis strain C95; 119602
• In Vitro Model: Streptococcus equisimilis strain C96; 119602
• In Vitro Model: Streptococcus pyogenes strain A498; 1314
• In Vitro Model: Streptococcus sp. strain G59; 1306
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The gene tet(T) was isolated from Streptococcus pyogenes A498, and the nucleotide sequence that was necessary and sufficient for the expression of tetracycline resistance in Escherichia coli was determined. The deduced Tet(T) protein consists of 651 amino acids. A phylogenetic analysis revealed that Tet T represents a novel branching order among the Tet determinants so far described.

Key Molecule: Tetracycline resistance protein TetS (TETS) [141], [142]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Minocycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Enterococcus spp. Isolates; 35783
• In Vitro Model: Streptococcus milleri isolates; 33040
• In Vitro Model: Streptococcus sanguis isolates; 1305
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: TetS confers tetracycline and minocycline resistance by ribosomal protection.

Moxifloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Quinolone efflux pump (QEPA2) [78]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A99G+p.V134I
• Resistant Drug: Moxifloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: QepA confers decreased susceptibility to hydrophilic fluoroquinolones (e.g., norfloxacin, ciprofloxacin, and enrofloxacin) with a 32- to 64-fold increase of MICs.

Nalidixic acid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside acetyltransferase (AAC) [22]

• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Nalidixic acid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83L
• Resistant Drug: Nalidixic acid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-112; 562
• In Vitro Model: Escherichia coli strain N-118; 562
• In Vitro Model: Escherichia coli strain N-119; 562
• In Vitro Model: Escherichia coli strain N-51; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83W
• Resistant Drug: Nalidixic acid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-18; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D87N
• Resistant Drug: Nalidixic acid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-113; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.G81C
• Resistant Drug: Nalidixic acid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-97; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A84P
• Resistant Drug: Nalidixic acid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-5; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A67S
• Resistant Drug: Nalidixic acid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-10; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Q106H
• Resistant Drug: Nalidixic acid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-89; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Netilmicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (AACC2) [118], [9]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Netilmicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Staphylococcus aureus ATCC 25923; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Various aminoglycoside modifying enzymes were associated with overlapping phenotypes: 36.5% strains produced AAC(6')-I with either a serine (GEN-TOB-NET) or a leucine (TOB-NET-AMk) at position 119, or both variants (GEN-TOB-NET-AMk); 21.2% expressed ANT(2")-I (GEN-TOB), 7.7% AAC(3)-II (GEN-TOB-NET), 5.8% AAC(3)-I (GEN) and 1.9% AAC(6')-II (GEN-TOB-NET-AMk) or AACA7 (TOB-NET-AMk).

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Netilmicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

Norfloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83L
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-112; 562
• In Vitro Model: Escherichia coli strain N-118; 562
• In Vitro Model: Escherichia coli strain N-119; 562
• In Vitro Model: Escherichia coli strain N-51; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83W
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-18; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D87N
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-113; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.G81C
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-97; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A84P
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-5; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A67S
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-10; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Q106H
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-89; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [74]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S463A
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [74]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S464Y
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [74]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S80I
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Quinolone efflux pump (QEPA2) [78]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A99G+p.V134I
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: QepA confers decreased susceptibility to hydrophilic fluoroquinolones (e.g., norfloxacin, ciprofloxacin, and enrofloxacin) with a 32- to 64-fold increase of MICs.

Novobiocin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA gyrase subunit B (GYRB) [143]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.R136C+p.R136H+p.R136S+p.G164V
• Resistant Drug: Novobiocin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Escherichia coli strain N4177; 562
• In Vitro Model: Escherichia coli strain CC1; 562
• In Vitro Model: Escherichia coli strain CC5; 562
• In Vitro Model: Escherichia coli strain LE234; 562
• In Vitro Model: Escherichia coli strain LE316; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Coumarins are inhibitors of the ATP hydrolysis and DNA supercoiling reactions catalysed by DNA gyrase. four mutations have been identified regaeding conferring coumarin resistance to Escherichia coli: Arg-136 to Cys, His or Ser and Gly-164 to Val.Significant differences in the susceptibility of mutant GyrB proteins to inhibition by either chlorobiocin and novobiocin or coumermycin have been found, suggesting wider contacts between coumermycin and GyrB.

Ofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA gyrase subunit A (GYRA) [71], [72]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T83I
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa ATCC10145; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: The major mechanism of the resistance of this Pseudomonas aeruginosa to fluoroquinolones is the modification of type II topoisomerases (DNA gyrase and topoisomerase IV).

Key Molecule: DNA gyrase subunit A (GYRA) [71], [72]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.H83R
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa ATCC10145; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: The major mechanism of the resistance of this Pseudomonas aeruginosa to fluoroquinolones is the modification of type II topoisomerases (DNA gyrase and topoisomerase IV).

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83L
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-112; 562
• In Vitro Model: Escherichia coli strain N-118; 562
• In Vitro Model: Escherichia coli strain N-119; 562
• In Vitro Model: Escherichia coli strain N-51; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S83W
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-18; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D87N
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-113; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.G81C
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-97; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A84P
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-5; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.A67S
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-10; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [75], [76], [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Q106H
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-89; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [74]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S463A
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [74]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S464Y
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [74]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.S80I
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug efflux pump Tap (TAP) [144], [145]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis H37Rv; 83332
• In Vitro Model: Mycobacterium tuberculosis ICC154; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: One mechanism proposed for drug resistance in Mycobacterium tuberculosis (MTB) is by efflux of the drugs by membrane located pumps.Mycobacterium tuberculosis isolate with a distinct genomic identity overexpresses a tap-like efflux pump,which confers resistance to Rifampin and Ofloxacin.

Key Molecule: Multidrug efflux pump Tap (TAP) [144], [145]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis H37Rv; 83332
• In Vitro Model: Mycobacterium tuberculosis ICC154; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: One mechanism proposed for drug resistance in Mycobacterium tuberculosis (MTB) is by efflux of the drugs by membrane located pumps.Mycobacterium tuberculosis isolate with a distinct genomic identity overexpresses a tap-like efflux pump,which confers resistance to Rifampin and Ofloxacin.

Key Molecule: Putative ABC transporter ATP-binding component (OTRC) [28]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli ET12567 (pUZ8002); 562
• In Vitro Model: Streptomyces rimosus M4018; 1927
• In Vitro Model: Streptomyces rimosus SR16; 1927
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: OtrC is a multidrug resistance protein based on an ATP hydrolysis-dependent active efflux mechanism.OtrC is a multidrug resistance protein based on an ATP hydrolysis-dependent active efflux mechanism.

Oxacillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [12], [13]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis H37Rv; 83332
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Mycobacterium smegmatis PM274; 1772
• In Vitro Model: Mycobacterium smegmatis PM759; 1772
• In Vitro Model: Mycobacterium smegmatis PM791; 1772
• In Vitro Model: Mycobacterium smegmatis PM876; 1772
• In Vitro Model: Mycobacterium smegmatis PM939; 1772
• In Vitro Model: Mycobacterium smegmatis PM976; 1772
• In Vitro Model: Mycobacterium tuberculosis PM638; 1773
• In Vitro Model: Mycobacterium tuberculosis PM669; 1773
• In Vitro Model: Mycobacterium tuberculosis PM670; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: Mycobacteria produce Beta-lactamases and are intrinsically resistant to Beta-lactam antibiotics.The mutants M. tuberculosis PM638 (detablaC1) and M. smegmatis PM759 (detablaS1) showed an increase in susceptibility to Beta-lactam antibiotics.

Key Molecule: Penicillin binding protein PBP 2 (PBP2) [45]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• In Vitro Model: Staphylococcus aureus M10/0061; 1280
• In Vitro Model: Staphylococcus aureus M10/0148; 1280
• In Vitro Model: Staphylococcus aureus WGB8404; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Disk diffusion test assay; Etest assay
• Mechanism Description: Methicillin resistance in staphylococci is mediated by penicillin binding protein 2a (PBP 2a), encoded by mecA on mobile staphylococcal cassette chromosome mec (SCCmec) elements.Whole-genome sequencing of one isolate (M10/0061) revealed a 30-kb SCCmec element encoding a class E mec complex with highly divergent blaZ-mecA-mecR1-mecI, a type 8 cassette chromosome recombinase (ccr) complex consisting of ccrA1-ccrB3, an arsenic resistance operon, and flanking direct repeats (DRs).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Tetracycline resistance protein class A (TETA) [146]

• Resistant Disease: Corynebacterium striatum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Oxacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum strain ATCC 13032; 196627
• In Vitro Model: Corynebacterium striatum strain M82B; 43770
• In Vitro Model: Escherichia coli strain DH5alphaMCR; 668369
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The large multiresistance plasmid pTP10 was initially identified in the clinical isolate C. striatum M82B. This 51-kb R-plasmid was shown to carry the determinants for resistance to the antibiotics chloramphenicol, erythomycin, kanamycin, and tetracycline by ethidium bromide-based curing experiments. The tetracycline and oxacillin resistance region is part of a DNA segment structurally similar to the chromosome of the human pathogen Mycobacterium tuberculosis. A resistance assay in C. glutamicum demonstrated that the tetAB gene pair of pTP10 is necessary to confer resistance to the antibiotics tetracycline and oxytetracycline.

Key Molecule: Tetracycline resistance protein class A (TETA) [146]

• Resistant Disease: Corynebacterium glutamicum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Oxacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum strain ATCC 13032; 196627
• In Vitro Model: Corynebacterium striatum strain M82B; 43770
• In Vitro Model: Escherichia coli strain DH5alphaMCR; 668369
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The large multiresistance plasmid pTP10 was initially identified in the clinical isolate C. striatum M82B. This 51-kb R-plasmid was shown to carry the determinants for resistance to the antibiotics chloramphenicol, erythomycin, kanamycin, and tetracycline by ethidium bromide-based curing experiments. Both resistance genes are located on mobile DNA elements that are capable of transposition into the chromosome of the non-pathogenic soil bacteriumC. glutamicum. A resistance assay in C. glutamicum demonstrated that the tetAB gene pair of pTP10 is necessary to confer resistance to the antibiotics tetracycline and oxytetracycline.

Oxytetracycline

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Tetracycline resistance protein tet(59) (TET59) [70]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxytetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli EPI-300; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Tet(59) is preceded by a homolog of the tetracycline repressor tetR typically found upstream of tet genes encoding efflux pumps and include the two palindromic operator sequences present in all regulatory regions of the tet(A)-tet(R) family (33), suggesting that tet(59) probably belongs to the efflux pump family.

Key Molecule: Putative ABC transporter ATP-binding component (OTRC) [28]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxytetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli ET12567 (pUZ8002); 562
• In Vitro Model: Streptomyces rimosus M4018; 1927
• In Vitro Model: Streptomyces rimosus SR16; 1927
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: OtrC is a multidrug resistance protein based on an ATP hydrolysis-dependent active efflux mechanism.OtrC is a multidrug resistance protein based on an ATP hydrolysis-dependent active efflux mechanism.

Key Molecule: Tetracycline resistance protein class A (TETA) [146]

• Resistant Disease: Corynebacterium striatum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Oxytetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum strain ATCC 13032; 196627
• In Vitro Model: Corynebacterium striatum strain M82B; 43770
• In Vitro Model: Escherichia coli strain DH5alphaMCR; 668369
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The large multiresistance plasmid pTP10 was initially identified in the clinical isolate C. striatum M82B. This 51-kb R-plasmid was shown to carry the determinants for resistance to the antibiotics chloramphenicol, erythomycin, kanamycin, and tetracycline by ethidium bromide-based curing experiments. The tetracycline and oxacillin resistance region is part of a DNA segment structurally similar to the chromosome of the human pathogen Mycobacterium tuberculosis. A resistance assay in C. glutamicum demonstrated that the tetAB gene pair of pTP10 is necessary to confer resistance to the antibiotics tetracycline and oxytetracycline.

Key Molecule: Tetracycline resistance protein class A (TETA) [146]

• Resistant Disease: Corynebacterium glutamicum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Oxytetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum strain ATCC 13032; 196627
• In Vitro Model: Corynebacterium striatum strain M82B; 43770
• In Vitro Model: Escherichia coli strain DH5alphaMCR; 668369
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The large multiresistance plasmid pTP10 was initially identified in the clinical isolate C. striatum M82B. This 51-kb R-plasmid was shown to carry the determinants for resistance to the antibiotics chloramphenicol, erythomycin, kanamycin, and tetracycline by ethidium bromide-based curing experiments. Both resistance genes are located on mobile DNA elements that are capable of transposition into the chromosome of the non-pathogenic soil bacteriumC. glutamicum. A resistance assay in C. glutamicum demonstrated that the tetAB gene pair of pTP10 is necessary to confer resistance to the antibiotics tetracycline and oxytetracycline.

Paromomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [116]

• Resistant Disease: Stenotrophomonas maltophilia infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Paromomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• Experiment for Molecule Alteration: PCR amplification assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Aph(3')-IIc significantly increases MICs of kanamycin, neomycin, butirosin, and paromomycin when expressed in Escherichia coli. Disruption of aph(3')-IIc results in decreased MICs of these drugs.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [7]

• Resistant Disease: Serratia marcescens infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Paromomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Piperacillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [14], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Piperacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli JM101; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Beta-lactamases (Beta-lactamhydrolase, EC 3.5.2.6), responsible for most of the resistance to Beta-lactam antibiotics, are often plasmid mediated.The OXA-1 beta-lactamase gene is part of Tn2603, which is borne on the R plasmid RGN238.

Key Molecule: Beta-lactamase (BLA) [16], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Piperacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli Gre-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The first extended-spectrum Beta-lactamase (ESBL) of the CTX-M type (MEN-1/CTX-M-1) was reported at the beginning of the 1990s.CTX-M-27 differed from CTX-M-14 only by the substitution D240G and was the third CTX-M enzyme harbouring this mutation after CTX-M-15 and CTX-M-16. The Gly-240-harbouring enzyme CTX-M-27 conferred to Escherichia coli higher MICs of ceftazidime (MIC, 8 versus 1 mg/L) than did the Asp-240-harbouring CTX-M-14 enzyme.

Key Molecule: Beta-lactamase (BLA) [15], [17], [18]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Piperacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Citrobacter freundii 2526/96; 546
• In Vitro Model: Escherichia coli isolates; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: We have reported recently the DNA sequence of another Beta-lactamase, CTX- M-15, from Indian enterobacterial isolates that were resistant to both cefotaxime and ceftazidime.CTX-M-15 has a single amino acid change [Asp-240-Gly (Ambler numbering)]7 compared with CTX-M-3.

Key Molecule: Metallo-beta-lactamase (VIM1) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Piperacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: A. xylosoxydans AX22 exhibited broad-spectrum resistance to Beta-lactams and aminoglycosides. The Beta-lactam resistance pattern (including piperacillin, ceftazidime, and carbapenem resistance) was unusual for this species, and the high-level carbapenem resistance suggested the production of an acquired carbapenemase. In fact, carbapenemase activity was detected in a crude extract of AX22 (specific activity, 184 +/- 12 U/mg of protein), and this activity was reduced (>80%) after incubation of the crude extract with 2 mM EDTA, suggesting the presence of a metallo-Beta-lactamase determinant.

Key Molecule: Beta-lactamase (BLA) [15], [23]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V77A+p.D114N+p.S140A+p.N288D
• Resistant Drug: Piperacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Citrobacter freundii strain 2524/96; 546
• In Vitro Model: Citrobacter freundii strain 2525/96; 546
• In Vitro Model: Citrobacter freundii strain 2526/96; 546
• In Vitro Model: Escherichia coli strain 2527/96; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Sequencing has revealed that C. freundii isolates produced a new CTX-M-3 enzyme which is very closely related to the CTX-M-1/MEN-1 Beta-lactamase.

Plazomicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [147], [148]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Plazomicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Staphylococcus aureus isolates; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: AAC(6')-APH(2") is an enzyme with 6'-N-acetyltransferase and 2"-O-phosphotransferase activities.The bifunctional AAC(6')-APH(2") has the capacity to inactivate virtually all clinically important aminoglycosides through N- and O-acetylation and phosphorylation of hydroxyl groups.

Ribostamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [7]

• Resistant Disease: Serratia marcescens infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ribostamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Rifampin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Rifampin phosphotransferase (RPHB) [35]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Rifampin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Paenibacillus sp. LC231; 1120679
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: RphB inactivates rifampin by Phosphorylation.

Key Molecule: rgt1438 (Unclear) [149]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Rifampin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces albus J1074; 457425
• In Vitro Model: Streptomyces speibonae WAC1438; 195801
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Rgt1438R encode a rifampin-inactivating glycosyltransferase,as a rifampin resistance determinant from WAC1438 capable of inactivating an assortment of rifamycins.

Key Molecule: Rifampin monooxygenase (IRI) [150]

• Resistant Disease: Rhodococcus equi infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain MM294; 562
• In Vitro Model: Rhodococcus equi strain ATCC 14887; 43767
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Monitored by zones of inhibition assay
• Mechanism Description: The original 8-kb clone and all subclones with the intact iri gene conferred similar 25-fold increases in rifampin resistance in rhodococcal strain Ri8. Clones growing on rifampin-containing selective plates all possessed an insert of about 8 kb, and retransformation into strain Ri8 demonstrated that this segment of DNA increased the rifampin MIC about 25-fold and conferred the ability to inactivate the antibiotic: rifampin at a concentration of 20 mg/ml was completely inactivated in about 6 h (as monitored by zones of inhibition on plates spread with a tester strain). inactivation gene cloned from the R.equi type strain, ATCC 14887, can confer a 10-fold increase in resistance to rifampin in E.coli as well as a 25-fold increase in Rhodococcus.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [151], [152]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; c.ins1593C
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli MG1655; 511145
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Frameshift mutations have been reported in rpoB, an essential gene encoding the beta-subunit of RNA polymerase, in rifampicin-resistant clinical isolates of Mycobacterium tuberculosis. Escherichia coli with a +1-nt frameshift mutation centrally located in rpoB is viable and highly resistant to rifampicin.

Rifamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Ribonucleic Acid Polymerase (RNAP) [153]

• Resistant Disease: Mycobacterium abscessus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Rifamycin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SOSP-9607 cells; Bones; Homo sapiens (Human); CVCL_4V80
• Experiment for Molecule Alteration: In vitro rifampicin ADP-ribosyl transferase activity assay; Rifampicin ADP-ribosyl transferase disk assay; Rifampicin ADP-ribosyl transferase MIC assay
• Mechanism Description: Rifamycin resistance is usually associated with mutations in RNAP that preclude rifamycin binding.

Rifapentine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Protein TetT (TETT) [140]

• Resistant Disease: Streptococcus pyogenes infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Rifapentine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain TG1; 562
• In Vitro Model: Streptococcus agalactiae strain B130; 1311
• In Vitro Model: Streptococcus anginosus strain MG16; 1328
• In Vitro Model: Streptococcus anginosus strain MG23; 1328
• In Vitro Model: Streptococcus anginosus strain MG32; 1328
• In Vitro Model: Streptococcus bovis strain D135; 1335
• In Vitro Model: Streptococcus bovis strain D295; 1335
• In Vitro Model: Streptococcus equisimilis strain C94; 119602
• In Vitro Model: Streptococcus equisimilis strain C95; 119602
• In Vitro Model: Streptococcus equisimilis strain C96; 119602
• In Vitro Model: Streptococcus pyogenes strain A498; 1314
• In Vitro Model: Streptococcus sp. strain G59; 1306
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The gene tet(T) was isolated from Streptococcus pyogenes A498, and the nucleotide sequence that was necessary and sufficient for the expression of tetracycline resistance in Escherichia coli was determined. The deduced Tet(T) protein consists of 651 amino acids. A phylogenetic analysis revealed that Tet T represents a novel branching order among the Tet determinants so far described.

Sisomicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [123]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Methylation; p.M7G1405
• Resistant Drug: Sisomicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• Experiment for Molecule Alteration: Protein-RNA footprinting assay
• Experiment for Drug Resistance: Isothermal titration calorimetry assay
• Mechanism Description: Sgm methylates G1405 in 16S rRNA to m7G, thereby rendering the ribosome resistant to 4, 6-disubstituted deoxystreptamine aminoglycosides.

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [2]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Intergeneric lateral gene transfer
• Resistant Drug: Sisomicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa AR-2; 287
• Experiment for Molecule Alteration: PCR screening assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The 16S rRNA methylase gene has undergone intergeneric horizontal gene transfer from some aminoglycoside producing microorganisms to Pseudomonas aeruginosa, which is called rmtA. rmtA protect bacterial 16S rRNA from intrinsic aminoglycosides by methylation.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(6')-acetyltransferase type 1 (A6AC1) [3]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sisomicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa Nk0001; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0002; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0003; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0004; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0005; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0006; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0007; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0008; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0009; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Micro-dilution method assay
• Mechanism Description: Recombinant AAC(6')-Iag protein showed aminoglycoside 6'-N-acetyltransferase activity using thin-layer chromatography (TLC) and MS spectrometric analysis. Escherichia coli carrying aac(6')-Iag showed resistance to amikacin, arbekacin, dibekacin, isepamicin, kanamycin, sisomicin, and tobramycin; but not to gentamicin.AAC(6')-Iag is a functional acetyltransferase that modifies alternate amino groups on the AGs.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [4]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Sisomicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• Experiment for Molecule Alteration: PCR mapping and sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Aac(3)-Ic gene could contribute to aminoglycoside resistance with a pattern typical of AAC(3)-I enzymes.

Key Molecule: Gentamicin 3'-acetyltransferase (AACC1) [128], [129]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sisomicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain BN; 562
• In Vitro Model: Escherichia coli strain J62; 562
• In Vitro Model: Escherichia coli strain k12 W3110; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: The most common mechanisms of resistance to aminoglycoside-aminocyclitol (AG) antibiotics in bacteria are exerted by enzymatic modification which results in failure of their binding to ribosomal targets and in prevention of uptake by the cell.

Spectinomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Spectinomycin 9-adenylyltransferase (ANT) [154], [155], [156]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Spectinomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus BD404; 1280
• In Vitro Model: Staphylococcus aureus RN4470; 1280
• In Vitro Model: Staphylococcus aureus RN4491; 1280
• In Vitro Model: Staphylococcus aureus RN4565; 1280
• In Vitro Model: Staphylococcus aureus RN4652; 1280
• In Vitro Model: Staphylococcus aureus RN4689; 1280
• In Vitro Model: Staphylococcus aureus RN4934; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The spc determinant encodes a unique adenyltransferase, AAD(9), that modifies spectinomycin but not streptomycin.

Key Molecule: Streptomycin 3''-adenylyltransferase (AADA27) [157]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Spectinomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter lwoffii VS15; 28090
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Pseudomonas sp. Tik3; 761262
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The genes aadA or ant(3")-1 encode streptomycin 3"-adenylyltransferase that mediates combined resistance to streptomycin and spectinomycin through an adenylation modification. aadA27 is a functionally active gene conferring high level of resistance to streptomycin and spectinomycin in the native A. lwoffii strain as well as in Escherichia coli.

Key Molecule: Spectinomycin 9-O-adenylyltransferase (ANT9) [158]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Spectinomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus ST398; 523796
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Downstream of the repN sequence was located a novel spectinomycin adenyltransferase gene, which was designated spd. The gene encoded a novel 257 amino acid protein, named Spd, which shared 47% identity with the spectinomycin adenyltransferase Aad9 from Enterococcus faecalis.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [22]

• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Spectinomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Key Molecule: AADA9 protein (AADA9) [159]

• Resistant Disease: Corynebacterium glutamicum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Spectinomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: AadA9 is a novel aminoglycoside adenyltransferase gene cassette which lead to drug resistance.

Spiramycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ErmR rRNA adenine N6-methyltransferase (ERMR) [88]

• Resistant Disease: Aeromicrobium erythreum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Spiramycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Aeromicrobium erythreum strains AR18; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1807; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1848; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1849; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1850; 2041
• In Vitro Model: Aeromicrobium erythreum strains BD170; 2041
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: Using the Ery- strain AR1807 as a recipient for plasmid-directed integrative recombination, the chromosomal ermR gene (encoding 23S rRNA methyltransferase) was disrupted, ermR-disrupted strains AR1848 and AR1849 were highly sensitive to erythromycin and the other macrolide antibiotics. Phenotypic characterizations demonstrated that ermR is the sole determinant of macrolide antibiotic resistance in A. erythreum. AR18, AR1807, and AR1850 (Ery- Ermr) were resistant to clindamycin, erythromycin, spiramycin, and tylosin (some sensitivity totylosin was observed at high concentrations).

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Macrolide 2'-phosphotransferase II (MPHB) [105], [106], [107]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Spiramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AG100A; 562
• In Vitro Model: Escherichia coli DB10; 562
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli XL1-Blue; 562
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Mph enzymes inactivate macrolides by phosphorylating the 2'-OH of the essential dimethylamino sugar, preventing it from binding the ribosome, and providing the chemical rationale for the resistance phenotype.

Streptomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Streptomycin 3''-adenylyltransferase (AADA27) [157]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Streptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter lwoffii VS15; 28090
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Pseudomonas sp. Tik3; 761262
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The genes aadA or ant(3")-1 encode streptomycin 3"-adenylyltransferase that mediates combined resistance to streptomycin and spectinomycin through an adenylation modification. aadA27 is a functionally active gene conferring high level of resistance to streptomycin and spectinomycin in the native A. lwoffii strain as well as in Escherichia coli.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [22]

• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Streptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Key Molecule: AADA9 protein (AADA9) [159]

• Resistant Disease: Corynebacterium glutamicum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Streptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: AadA9 is a novel aminoglycoside adenyltransferase gene cassette which lead to drug resistance.

Key Molecule: Aminoglycoside 6-adenylyltransferase (A6AD) [160], [161]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Streptomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Bacillus subtilis strain 168; 1423
• In Vitro Model: Bacillus subtilis strain 169; 1423
• In Vitro Model: Bacillus subtilis strain 170; 1423
• In Vitro Model: Bacillus subtilis strain 171; 1423
• In Vitro Model: Bacillus subtilis strain 172; 1423
• In Vitro Model: Bacillus subtilis strain 173; 1423
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: B. subtilis 168 produce s a chromosomally encoded aminoglycoside 6-adenylyltransferase, AAD(6),which inactivates S M by adenylation at the C-6 position of streptomycin.

Key Molecule: Aminoglycoside 6-adenylyltransferase AadS (AAADS) [162]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Streptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bacteroides fragilis strain IB131; 817
• In Vitro Model: Bacteroides ovatus strains IB106; 28116
• In Vitro Model: Bacteroides ovatus strains IB136; 28116
• In Vitro Model: Bacteroides uniformis strain IB128; 820
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The aadS-encoded peptide displayed significant homology to Gram-positive streptomycin-dependent adenyltransferases, and enzymatic analysis confirmed the production of this activity.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: TolC family outer membrane protein (TOLC) [10]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Streptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AYE WT; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO Omega abuO; 509173
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: AbuO, an OMP, confers broad-spectrum antimicrobial resistance via active efflux in A. baumannii.

Tazobactam

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (Q6QJ55) [163]

• Resistant Disease: Carbapenem-nonsusceptible Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Function; Inhibition
• Resistant Drug: Tazobactam
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Carbapenem-nonsusceptible Pseudomonas aeruginosa strain; 287
• Experiment for Molecule Alteration: Whole-genome sequencing assay
• Mechanism Description: Ceftolozane/tazobactam (C/T), a novel beta-lactam/beta-lactamase inhibitor combination, addresses an unmet medical need in patients with these multidrug-resistant P. aeruginosa infections.

Telithromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase ermE (ERME) [79], [80], [81]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Telithromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli AS19-RrmA-; 562
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli JC7623; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Methylation of specific nucleotides in rRNA is one of the means by which bacteria achieve resistance to macrolides-lincosamides-streptogramin B (MLSB) and ketolide antibiotics.ErmE dimethylation confers high resistance to all the MLSB and ketolide drugs.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Macrolide 2'-phosphotransferase II (MPHB) [105], [106], [107]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Telithromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AG100A; 562
• In Vitro Model: Escherichia coli DB10; 562
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli XL1-Blue; 562
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Mph enzymes inactivate macrolides by phosphorylating the 2'-OH of the essential dimethylamino sugar, preventing it from binding the ribosome, and providing the chemical rationale for the resistance phenotype.

Tetracycline

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tetracycline resistance protein Tet (TETW/N/W) [70]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli EPI-300; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Tet(W/N/W) encodes mosaic ribosomal protection(since tetracyclines bind to the 30S ribosomal subunit to inhibit protein translation) and induces resistance.

Key Molecule: Tetracycline resistance protein TetM (TETM) [164]

• Resistant Disease: Enterococci infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis OG1RF:pCF10; 474186
• In Vitro Model: Enterococcus faecalis OG1SSp; 1351
• In Vivo Model: House fly model; House fly
• Experiment for Molecule Alteration: Bacterial colonies count assay
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: Tetracycline resistance of Musca domestica occurred by transferring the plasmid transduced with tetracycline resistance gene TETM of Enterococcus into Musca domestica.

Key Molecule: Tetracycline resistance protein TetW (TETW) [165]

• Resistant Disease: Butyrivibrio fibrisolvens infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bifidobacterium longum strain F10; 216816
• In Vitro Model: Bifidobacterium longum strain F5; 216816
• In Vitro Model: Bifidobacterium longum strain F8; 216816
• In Vitro Model: Butyrivibrio fibrisolvens strain 1.23; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain 1.230; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain Jk214; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain Jk51; 831
• In Vitro Model: Fusobacterium prausnitzii strain k10; 853
• In Vitro Model: Mitsuokella multiacidus strain 46/5(2); 52226
• In Vitro Model: Mitsuokella multiacidus strain P208-58; 52226
• In Vitro Model: Selenomonas ruminantium strain FB32; 971
• In Vitro Model: Selenomonas ruminantium strain FB322; 971
• In Vitro Model: Selenomonas ruminantium strain FB34; 971
• Experiment for Molecule Alteration: Southern blotting assay
• Mechanism Description: Members of our group recently identified a new tetracycline resistance gene, tet(W), in three genera of rumen obligate anaerobes. Here, we show that tet(W) is also present in bacteria isolated from human feces. The tet(W) genes found in human Fusobacterium prausnitzii and Bifidobacterium longum isolates were more than 99.9% identical to those from a rumen isolate of Butyrivibrio fibrisolvens.

Key Molecule: Tetracycline resistance protein TetW (TETW) [165]

• Resistant Disease: Selenomonas ruminantium infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bifidobacterium longum strain F10; 216816
• In Vitro Model: Bifidobacterium longum strain F5; 216816
• In Vitro Model: Bifidobacterium longum strain F8; 216816
• In Vitro Model: Butyrivibrio fibrisolvens strain 1.23; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain 1.230; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain Jk214; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain Jk51; 831
• In Vitro Model: Fusobacterium prausnitzii strain k10; 853
• In Vitro Model: Mitsuokella multiacidus strain 46/5(2); 52226
• In Vitro Model: Mitsuokella multiacidus strain P208-58; 52226
• In Vitro Model: Selenomonas ruminantium strain FB32; 971
• In Vitro Model: Selenomonas ruminantium strain FB322; 971
• In Vitro Model: Selenomonas ruminantium strain FB34; 971
• Experiment for Molecule Alteration: Southern blotting assay
• Mechanism Description: Members of our group recently identified a new tetracycline resistance gene, tet(W), in three genera of rumen obligate anaerobes. Here, we show that tet(W) is also present in bacteria isolated from human feces. The tet(W) genes found in human Fusobacterium prausnitzii and Bifidobacterium longum isolates were more than 99.9% identical to those from a rumen isolate of Butyrivibrio fibrisolvens.

Key Molecule: Tetracycline resistance protein TetW (TETW) [165]

• Resistant Disease: Mitsuokella multiacidus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bifidobacterium longum strain F10; 216816
• In Vitro Model: Bifidobacterium longum strain F5; 216816
• In Vitro Model: Bifidobacterium longum strain F8; 216816
• In Vitro Model: Butyrivibrio fibrisolvens strain 1.23; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain 1.230; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain Jk214; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain Jk51; 831
• In Vitro Model: Fusobacterium prausnitzii strain k10; 853
• In Vitro Model: Mitsuokella multiacidus strain 46/5(2); 52226
• In Vitro Model: Mitsuokella multiacidus strain P208-58; 52226
• In Vitro Model: Selenomonas ruminantium strain FB32; 971
• In Vitro Model: Selenomonas ruminantium strain FB322; 971
• In Vitro Model: Selenomonas ruminantium strain FB34; 971
• Experiment for Molecule Alteration: Southern blotting assay
• Mechanism Description: Members of our group recently identified a new tetracycline resistance gene, tet(W), in three genera of rumen obligate anaerobes. Here, we show that tet(W) is also present in bacteria isolated from human feces. The tet(W) genes found in human Fusobacterium prausnitzii and Bifidobacterium longum isolates were more than 99.9% identical to those from a rumen isolate of Butyrivibrio fibrisolvens.

Key Molecule: Tetracycline resistance protein TetW (TETW) [165]

• Resistant Disease: Fusobacterium prausnitzii infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bifidobacterium longum strain F10; 216816
• In Vitro Model: Bifidobacterium longum strain F5; 216816
• In Vitro Model: Bifidobacterium longum strain F8; 216816
• In Vitro Model: Butyrivibrio fibrisolvens strain 1.23; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain 1.230; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain Jk214; 831
• In Vitro Model: Butyrivibrio fibrisolvens strain Jk51; 831
• In Vitro Model: Fusobacterium prausnitzii strain k10; 853
• In Vitro Model: Mitsuokella multiacidus strain 46/5(2); 52226
• In Vitro Model: Mitsuokella multiacidus strain P208-58; 52226
• In Vitro Model: Selenomonas ruminantium strain FB32; 971
• In Vitro Model: Selenomonas ruminantium strain FB322; 971
• In Vitro Model: Selenomonas ruminantium strain FB34; 971
• Experiment for Molecule Alteration: Southern blotting assay
• Mechanism Description: Members of our group recently identified a new tetracycline resistance gene, tet(W), in three genera of rumen obligate anaerobes. Here, we show that tet(W) is also present in bacteria isolated from human feces. The tet(W) genes found in human Fusobacterium prausnitzii and Bifidobacterium longum isolates were more than 99.9% identical to those from a rumen isolate of Butyrivibrio fibrisolvens.

Key Molecule: Tetracycline resistance protein TetS (TETS) [141], [142]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Enterococcus spp. Isolates; 35783
• In Vitro Model: Streptococcus milleri isolates; 33040
• In Vitro Model: Streptococcus sanguis isolates; 1305
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: TetS confers tetracycline and minocycline resistance by ribosomal protection.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: acrB-acrA (Unclear) [166]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tetracycline
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: High-throughput sequencing assay
• Mechanism Description: Relative abundance of ARGs was significantly increased under high oxytetracycline concentration. Of the 36 ARG-carrying contigs in the OTC-25 plasmidome, 20 were matched in the NCBI Plasmid Genome Database, with 17 carrying multiple ARGs (carrying >= 2 ARGs), including gene combinations of pecM-tetA-tetR-qnrS1, tet31-tetR(31) (tetR(31), which is used to regulate the expression of tet31 gene, is one kind of tetR (tetracycline repressor gene)), floR-sul1, strA-strB, acrB-acrA, ATP-binding cassette transporter (ABC transporter)-ABC transporter, and mexC.

Key Molecule: Protein PecM (PeECM) [166]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tetracycline
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: High-throughput sequencing assay
• Mechanism Description: Relative abundance of ARGs was significantly increased under high oxytetracycline concentration. Of the 36 ARG-carrying contigs in the OTC-25 plasmidome, 20 were matched in the NCBI Plasmid Genome Database, with 17 carrying multiple ARGs (carrying >= 2 ARGs), including gene combinations of pecM-tetA-tetR-qnrS1, tet31-tetR(31) (tetR(31), which is used to regulate the expression of tet31 gene, is one kind of tetR (tetracycline repressor gene)), floR-sul1, strA-strB, acrB-acrA, ATP-binding cassette transporter (ABC transporter)-ABC transporter, and mexC.

Key Molecule: Major facilitator superfamily MFS_1 (TETV) [167], [168], [169]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium abscessus OS11; 36809
• In Vitro Model: Mycobacterium abscessus OS13; 36809
• In Vitro Model: Mycobacterium fortuitum OS2/7; 1766
• In Vitro Model: Mycobacterium fortuitum OS21; 1766
• In Vitro Model: Mycobacterium fortuitum OS24; 1766
• In Vitro Model: Mycobacterium fortuitum OS25; 1766
• In Vitro Model: Mycobacterium fortuitum OS28; 1766
• In Vitro Model: Mycobacterium fortuitum OS30; 1766
• In Vitro Model: Mycobacterium fortuitum OS8; 1766
• In Vitro Model: Mycobacterium fortuitum OS9; 1766
• In Vitro Model: Mycobacterium fortuitum TR-1378; 1766
• In Vitro Model: Mycobacterium mucogenicum OS11; 56689
• In Vitro Model: Mycobacterium peregrinum OS2/8; 43304
• In Vitro Model: Mycobacterium smegmatis OS1; 1772
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: Tetracycline/multidrug efflux pumps Tet(V) and Tap may belong to this intrinsic resistome as they have been so far found only in certain RGM species.tet(V) and tap, both encode mycobacterial efflux pumps, including species where these genes have never been evidenced before.

Key Molecule: Tetracycline resistance protein class A (TETA) [167], [170]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli LM317; 562
• In Vitro Model: Escherichia coli TB1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The bacterial tetracycline-resistance determinant from Tn10 encodes a 43 kDa membrane protein, TetA, responsible for active efflux of tetracyclines.

Key Molecule: ARE-ABC-F family resistance factor PoxtA (POXTA) [64]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Escherichia coli Mach1 T1R; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth dilution test assay
• Mechanism Description: The poxtA gene encodes a protein that is 32% identical to OptrA and exhibits structural features typical of the F lineage of the ATP-binding cassette (ABC) protein superfamily that cause antibiotic resistance by ribosomal protection.

Key Molecule: Tetracycline resistance protein class A48 (TETA48) [35]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Paenibacillus sp. LC231; 1120679
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Two predicted ABC-transporters that confer resistance to tetracycline (TetAB(48)) and tiamulin (TaeA).

Key Molecule: Tetracycline resistance protein tet(59) (TET59) [70]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli EPI-300; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Tet(59) is preceded by a homolog of the tetracycline repressor tetR typically found upstream of tet genes encoding efflux pumps and include the two palindromic operator sequences present in all regulatory regions of the tet(A)-tet(R) family (33), suggesting that tet(59) probably belongs to the efflux pump family.

Key Molecule: Tetracycline efflux protein TetA (TETA) [159]

• Resistant Disease: Corynebacterium glutamicum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Tet33 causes tetracycline resistance by regulating tetracycline efflux.

Key Molecule: Tetracycline efflux Na+/H+ antiporter family transporter Tet(35) (TEE35) [171]

• Resistant Disease: Vibrio harveyi infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli TOP 10; 83333
• In Vitro Model: Vibrio harveyi M3.4L; 669
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Agar dilution technique assay
• Mechanism Description: We describe the cloning and characterization of two tetracycline resistance determinants from V. harveyi strain M3.4L. The second determinant, cloned as a 3,358-bp fragment in pATJ1, contains two open reading frames, designated tet35 and txr. tet35 encodes a 369-amino-acid protein that was predicted to have nine transmembrane regions. Tetracycline accumulation studies indicate that Escherichia coli carrying tet35 and txr can function as an energy-dependent tetracycline efflux pump but is less efficient than TetA.

Key Molecule: Tetracycline resistance protein class A (TETA) [146]

• Resistant Disease: Corynebacterium striatum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum strain ATCC 13032; 196627
• In Vitro Model: Corynebacterium striatum strain M82B; 43770
• In Vitro Model: Escherichia coli strain DH5alphaMCR; 668369
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The large multiresistance plasmid pTP10 was initially identified in the clinical isolate C. striatum M82B. This 51-kb R-plasmid was shown to carry the determinants for resistance to the antibiotics chloramphenicol, erythomycin, kanamycin, and tetracycline by ethidium bromide-based curing experiments. The tetracycline and oxacillin resistance region is part of a DNA segment structurally similar to the chromosome of the human pathogen Mycobacterium tuberculosis. A resistance assay in C. glutamicum demonstrated that the tetAB gene pair of pTP10 is necessary to confer resistance to the antibiotics tetracycline and oxytetracycline.

Key Molecule: Tetracycline resistance protein class A (TETA) [146]

• Resistant Disease: Corynebacterium glutamicum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum strain ATCC 13032; 196627
• In Vitro Model: Corynebacterium striatum strain M82B; 43770
• In Vitro Model: Escherichia coli strain DH5alphaMCR; 668369
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The large multiresistance plasmid pTP10 was initially identified in the clinical isolate C. striatum M82B. This 51-kb R-plasmid was shown to carry the determinants for resistance to the antibiotics chloramphenicol, erythomycin, kanamycin, and tetracycline by ethidium bromide-based curing experiments. Both resistance genes are located on mobile DNA elements that are capable of transposition into the chromosome of the non-pathogenic soil bacteriumC. glutamicum. A resistance assay in C. glutamicum demonstrated that the tetAB gene pair of pTP10 is necessary to confer resistance to the antibiotics tetracycline and oxytetracycline.

Key Molecule: Tetracycline efflux protein tet(L) (TETL) [167], [172]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tetracycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain Sk1592; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Gradient plate method assay
• Mechanism Description: The class L determinant, on the other hand, does not prevent the inhibition of protein synthesis in S. faecalis but rather decreases tetracycline uptake.The class L (TetL) tetracycline resistance determinant from streptococci specified resistance and an energy-dependent decreased accumulation of tetracycline in both Streptococcus faecalis and Escherichia coli.

Thiacetazone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [173]

• Resistant Disease: Mycobacterium abscessus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Thiacetazone
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium abscessus strain CIP104536T; 36809
• In Vitro Model: Mycobacterium bolletii strain CIP108541T; 319705
• In Vitro Model: Mycobacterium massiliense strain CIP108297T; 319705
• Experiment for Molecule Alteration: Whole-genome sequencing assay
• Experiment for Drug Resistance: Microdilution method
• Mechanism Description: TAC, like ethionamide, requires activation by the flavin-containing monooxygenase EthA. EthR, whose gene is adjacent to ethA in M. tuberculosis and in M. smegmatis, represses the transcription of ethA, subsequently preventing the conversion of the prodrugs to active molecules. EthR belongs to the TetR/CamR family of transcriptional regulators that negatively regulates the expression of EthA.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Siderophore exporter (MMPL5) [173]

• Resistant Disease: Mycobacterium abscessus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Thiacetazone
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium abscessus strain CIP104536T; 36809
• In Vitro Model: Mycobacterium bolletii strain CIP108541T; 319705
• In Vitro Model: Mycobacterium massiliense strain CIP108297T; 319705
• Experiment for Molecule Alteration: Whole-genome sequencing assay
• Experiment for Drug Resistance: Microdilution method
• Mechanism Description: Importantly, mutations in the transcriptional TetR repressor MAB_4384, with concomitant upregulation of the divergently oriented adjacent genes encoding an MmpS5/MmpL5 efflux pump system, accounted for high cross-resistance levels among all three compounds.

Key Molecule: Siderophore export accessory protein MmpS5 (mmpS5) [173]

• Resistant Disease: Mycobacterium abscessus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Thiacetazone
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium abscessus strain CIP104536T; 36809
• In Vitro Model: Mycobacterium bolletii strain CIP108541T; 319705
• In Vitro Model: Mycobacterium massiliense strain CIP108297T; 319705
• Experiment for Molecule Alteration: Whole-genome sequencing assay
• Experiment for Drug Resistance: Microdilution method
• Mechanism Description: Importantly, mutations in the transcriptional TetR repressor MAB_4384, with concomitant upregulation of the divergently oriented adjacent genes encoding an MmpS5/MmpL5 efflux pump system, accounted for high cross-resistance levels among all three compounds.

Thiethylperazine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Vancomycin/teicoplanin A-type resistance protein VanA (VANA) [174]

• Sensitive Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Sensitive Drug: Thiethylperazine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecium strain; 1352
• In Vitro Model: Streptococcus faecium strain; 1352
• Experiment for Drug Resistance: agar dilution method
• Mechanism Description: Resistance to vancomycin in enterococci is mainly caused by expression of enzymes such as ligase, dehydrogenase, carboxypeptidase and carboxypeptidase which are encoded by genes such as vanA and vanB. Phenothiazines such as chlorpromazine are well known to deactivate a large number of enzymes. The reversal of vancomycin resistance may be due to enzyme inactivation.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: D-alanine--D-alanine ligase (Q5MPQ2) [174]

• Sensitive Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Sensitive Drug: Thiethylperazine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecium strain; 1352
• In Vitro Model: Streptococcus faecium strain; 1352
• Experiment for Drug Resistance: agar dilution method
• Mechanism Description: Resistance to vancomycin in enterococci is mainly caused by expression of enzymes such as ligase, dehydrogenase, carboxypeptidase and carboxypeptidase which are encoded by genes such as vanA and vanB. Phenothiazines such as chlorpromazine are well known to deactivate a large number of enzymes. The reversal of vancomycin resistance may be due to enzyme inactivation.

Tiamulin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Carboxymethylenebutenolidase (CLCD) [84]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tiamulin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli AS19; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The Cfr RNA methyltransferase causes multiple resistances to peptidyl transferase inhibitors by methylation of A2503 23S rRNA.clcD codes the same enzyme.

Key Molecule: Ribosomal RNA large subunit methyltransferase (CFR ) [85]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tiamulin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Cfr confers resistance to antibiotics binding to the peptidyl transferase center on the ribosome.The primary product of the Cfr-mediated methylation is 8-methyladenosine (m8A), a new natural RNA modification that has so far not been seen at sites other than A2503 in 23S rRNA.

Key Molecule: 23S rRNA (Adenine(2503)-C(8))-methyltransferase ClbA (CIBA) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tiamulin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter ATP-binding protein (ABCP) [89], [90]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T450I
• Resistant Drug: Tiamulin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Enterococcus faecium HM1070; 1352
• In Vitro Model: Enterococcus faecium UCN80; 1352
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: ABC systems constitute one of the largest families of proteins, with most of them being involved in import and export, often called ABC transporters.Several of these class 2 ABC systems have been involved in MLS resistance, such as Msr-, Vga-, or Lsa-like proteins.The observed profile of cross-resistance to lincosamides, streptogramins A, and pleuromutilins conferred by Eat(A)v was similar to those conferred by other Lsa-like proteins.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Colibactin polyketide synthase ClbC (CLBC) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tiamulin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Ticarcillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• Resistant Drug: Ticarcillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Acinetobacter baumannii CIP70.10; 470
• In Vitro Model: Klebsiella pneumoniae kP3; 1290996
• In Vitro Model: Pseudomonas aeruginosa PU21; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: K. pneumoniae kP3 was resistant to all Beta-lactams, including carbapenems, and expressed the carbapenem-hydrolyzing Beta-lactamase OXA-181, which differs from OXA-48 by four amino acid substitutions. Compared to OXA-48, OXA-181 possessed a very similar hydrolytic profile.

Key Molecule: Metallo-beta-lactamase NDM-4 (NDM4) [175]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.M154L
• Resistant Drug: Ticarcillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli I5; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: A clinical Escherichia coli isolate resistant to all Beta-lactams, including carbapenems, expressed a novel metallo-Beta-lactamase (MBL), NDM-4, differing from NDM-1 by a single amino acid substitution (Met154Leu). NDM-4 possessed increased hydrolytic activity toward carbapenems and several cephalosporins compared to that of NDM-1.

Key Molecule: Beta-lactamase (BLA) [16], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Ticarcillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli Gre-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The first extended-spectrum Beta-lactamase (ESBL) of the CTX-M type (MEN-1/CTX-M-1) was reported at the beginning of the 1990s.CTX-M-27 differed from CTX-M-14 only by the substitution D240G and was the third CTX-M enzyme harbouring this mutation after CTX-M-15 and CTX-M-16. The Gly-240-harbouring enzyme CTX-M-27 conferred to Escherichia coli higher MICs of ceftazidime (MIC, 8 versus 1 mg/L) than did the Asp-240-harbouring CTX-M-14 enzyme.

Key Molecule: Beta-lactamase (BLA) [15], [17], [18]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D240G
• Resistant Drug: Ticarcillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Citrobacter freundii 2526/96; 546
• In Vitro Model: Escherichia coli isolates; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: We have reported recently the DNA sequence of another Beta-lactamase, CTX- M-15, from Indian enterobacterial isolates that were resistant to both cefotaxime and ceftazidime.CTX-M-15 has a single amino acid change [Asp-240-Gly (Ambler numbering)]7 compared with CTX-M-3.

Tigecycline

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Flavin-dependent monooxygenase (TETX4) [176]

• Resistant Disease: Acinetobacter specie infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tigecycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii 34AB; 509173
• In Vitro Model: Escherichia coli 47EC; 562
• In Vivo Model: ICR female mice model; Mus musculus
• Experiment for Molecule Alteration: Genome extraction and sequencing assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Two unique mobile tigecycline-resistance genes,Tet(X3) and Tet(X4), inactivate all tetracyclines, including tigecycline and the newly FDA-approved eravacycline and omadacycline.

Key Molecule: Flavin-dependent monooxygenase (TETX4) [176]

• Resistant Disease: Enterobacteriaceae infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tigecycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii 34AB; 509173
• In Vitro Model: Escherichia coli 47EC; 562
• In Vivo Model: ICR female mice model; Mus musculus
• Experiment for Molecule Alteration: Genome extraction and sequencing assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Two unique mobile tigecycline-resistance genes,Tet(X3) and Tet(X4), inactivate all tetracyclines, including tigecycline and the newly FDA-approved eravacycline and omadacycline.

Key Molecule: Flavin-dependent monooxygenase (TETX3) [176]

• Resistant Disease: Acinetobacter specie infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tigecycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii 34AB; 509173
• In Vitro Model: Escherichia coli 47EC; 562
• In Vivo Model: ICR female mice model; Mus musculus
• Experiment for Molecule Alteration: Genome extraction and sequencing assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Tet(X3) and Tet(X4) inactivate all tetracyclines, including tigecycline and the newly FDA-approved eravacycline and omadacycline.

Key Molecule: Flavin-dependent monooxygenase (TETX3) [176]

• Resistant Disease: Enterobacteriaceae infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tigecycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii 34AB; 509173
• In Vitro Model: Escherichia coli 47EC; 562
• In Vivo Model: ICR female mice model; Mus musculus
• Experiment for Molecule Alteration: Genome extraction and sequencing assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Tet(X3) and Tet(X4) inactivate all tetracyclines, including tigecycline and the newly FDA-approved eravacycline and omadacycline.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: TolC family outer membrane protein (TOLC) [10]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tigecycline
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AYE WT; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO Omega abuO; 509173
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: AbuO, an OMP, confers broad-spectrum antimicrobial resistance via active efflux in A. baumannii.

Tobramycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [2]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Intergeneric lateral gene transfer
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa AR-2; 287
• Experiment for Molecule Alteration: PCR screening assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The 16S rRNA methylase gene has undergone intergeneric horizontal gene transfer from some aminoglycoside producing microorganisms to Pseudomonas aeruginosa, which is called rmtA. rmtA protect bacterial 16S rRNA from intrinsic aminoglycosides by methylation.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: AacA43 aminoglycoside (AACA43) [133]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Klebsiella pneumoniae LT12; 573
• In Vitro Model: Klebsiella pneumoniae SSI2.46; 573
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Like related aminoglycoside-(6')-acetyltransferases, AacA43 confers clinically relevant resistance to kanamycin, tobramycin, and some less-used aminoglycosides but not to gentamicin.

Key Molecule: Aminoglycoside N(3)-acetyltransferase (AACC2) [118], [9]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Staphylococcus aureus ATCC 25923; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Various aminoglycoside modifying enzymes were associated with overlapping phenotypes: 36.5% strains produced AAC(6')-I with either a serine (GEN-TOB-NET) or a leucine (TOB-NET-AMk) at position 119, or both variants (GEN-TOB-NET-AMk); 21.2% expressed ANT(2")-I (GEN-TOB), 7.7% AAC(3)-II (GEN-TOB-NET), 5.8% AAC(3)-I (GEN) and 1.9% AAC(6')-II (GEN-TOB-NET-AMk) or AACA7 (TOB-NET-AMk).

Key Molecule: Aminoglycoside adenyltransferase 2''-Ia (ANT2I) [126], [127]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AB5075; 1116234
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: ANT(2")-Ia confers resistance by magnesium-dependent transfer of a nucleoside monophosphate (AMP) to the 2"-hydroxyl of aminoglycoside substrates containing a 2-deoxystreptamine core.

Key Molecule: Aminoglycoside N(6')-acetyltransferase type 1 (A6AC1) [3]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa Nk0001; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0002; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0003; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0004; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0005; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0006; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0007; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0008; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0009; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Micro-dilution method assay
• Mechanism Description: Recombinant AAC(6')-Iag protein showed aminoglycoside 6'-N-acetyltransferase activity using thin-layer chromatography (TLC) and MS spectrometric analysis. Escherichia coli carrying aac(6')-Iag showed resistance to amikacin, arbekacin, dibekacin, isepamicin, kanamycin, sisomicin, and tobramycin; but not to gentamicin.AAC(6')-Iag is a functional acetyltransferase that modifies alternate amino groups on the AGs.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [4]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• Experiment for Molecule Alteration: PCR mapping and sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Aac(3)-Ic gene could contribute to aminoglycoside resistance with a pattern typical of AAC(3)-I enzymes.

Key Molecule: AAC(6')-Ib family aminoglycoside 6'-N-acetyltransferase (AAC6IB) [130]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Escherichia coli k-12; 83333
• In Vitro Model: Pseudomonas aeruginosa Pa695; 287
• Experiment for Molecule Alteration: PCR experiments assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: The fusion product was functional, as was the product of each gene cloned separately: AAC(3)-I, despite the deletion of the four last amino acids, and AAC(6"), which carried three amino acid changes compared with the most homologous sequence. The AAC(3)-I protein conferred an expected gentamicin and fortimicin resistance, and the AAC(6"), despite the Leu-119-Ser substitution, yielded resistance to kanamycin, tobramycin, and dibekacin, but slightly affected netilmicin and amikacin, and had no apparent effect on gentamicin. The fusion product conveyed a large profile of resistance, combining the AAC(6") activity with a higher level of gentamicin resistance without accompanying fortimicin resistance.

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

Key Molecule: Aminoglycoside N(6')-acetyltransferase type 1 (A6AC1) [121], [122]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM83; 562
• In Vitro Model: Escherichia coli strain k802N; 562
• In Vitro Model: Pseudomonas aeruginosa strain BM2692; 287
• In Vitro Model: Pseudomonas aeruginosa strain BM2693; 287
• In Vitro Model: Pseudomonas aeruginosa strain BM2694; 287
• In Vitro Model: Pseudomonas aeruginosa strain BM2695; 287
• In Vitro Model: Pseudomonas fluorescens strain BM2687; 294
• In Vitro Model: Pseudomonas fluorescens strain BM2687-1; 294
• In Vitro Model: Pseudomonas fluorescens strain BM2687-2; 294
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: The aac(6')-Ib' gene from Pseudomonas fluorescens BM2687, encoding an aminoglycoside 6'-N-acetyltransferase type II which confers resistance to gentamicin but not to amikacin, was characterized.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Chaperone protein ClpB (CLPB) [177]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tobramycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Pseudomonas aeruginosa MPAO1; 1131757
• Experiment for Molecule Alteration: SRM analysis
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The extracellular polysaccharide layer of biofilm can prolong the time of bactericide penetration into the central cell cluster. The proteomic response of Pseudomonas aeruginosa depends on the level of tobramycin experienced by the cells after exposure to various sub inhibitory levels (0.1-1) u Tobramycin (g / ml) can induce different proteins. Bacterial cells exposed to low levels of tobramycin showed elevated levels of enzymes that metabolize and synthesize amino acids that may alter drug sensitivity. Inactivation of ibpA did not yield significant tobramycin MIC changes. However, inactivation of two heat shock proteins/proteases ibpA/clpB, ibpA/PA0779, or ibpA/hslV led to increased tobramycin sensitivity changes in P. aeruginosa.

Key Molecule: ATP-dependent protease subunit HslV (HSlV) [177]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tobramycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Pseudomonas aeruginosa MPAO1; 1131757
• Experiment for Molecule Alteration: SRM analysis
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The extracellular polysaccharide layer of biofilm can prolong the time of bactericide penetration into the central cell cluster. The proteomic response of Pseudomonas aeruginosa depends on the level of tobramycin experienced by the cells after exposure to various sub inhibitory levels (0.1-1) u Tobramycin (g / ml) can induce different proteins. Bacterial cells exposed to low levels of tobramycin showed elevated levels of enzymes that metabolize and synthesize amino acids that may alter drug sensitivity. Inactivation of ibpA did not yield significant tobramycin MIC changes. However, inactivation of two heat shock proteins/proteases ibpA/clpB, ibpA/PA0779, or ibpA/hslV led to increased tobramycin sensitivity changes in P. aeruginosa.

Key Molecule: Heat-shock protein IbpA (IBPA) [177]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tobramycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Pseudomonas aeruginosa MPAO1; 1131757
• Experiment for Molecule Alteration: SRM analysis
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The extracellular polysaccharide layer of biofilm can prolong the time of bactericide penetration into the central cell cluster. The proteomic response of Pseudomonas aeruginosa depends on the level of tobramycin experienced by the cells after exposure to various sub inhibitory levels (0.1-1) u Tobramycin (g / ml) can induce different proteins. Bacterial cells exposed to low levels of tobramycin showed elevated levels of enzymes that metabolize and synthesize amino acids that may alter drug sensitivity. Inactivation of ibpA did not yield significant tobramycin MIC changes. However, inactivation of two heat shock proteins/proteases ibpA/clpB, ibpA/PA0779, or ibpA/hslV led to increased tobramycin sensitivity changes in P. aeruginosa.

Key Molecule: Lon protease (LON) [177]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tobramycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Pseudomonas aeruginosa MPAO1; 1131757
• Experiment for Molecule Alteration: SRM analysis
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The extracellular polysaccharide layer of biofilm can prolong the time of bactericide penetration into the central cell cluster. The proteomic response of Pseudomonas aeruginosa depends on the level of tobramycin experienced by the cells after exposure to various sub inhibitory levels (0.1-1) u Tobramycin (g / ml) can induce different proteins. Bacterial cells exposed to low levels of tobramycin showed elevated levels of enzymes that metabolize and synthesize amino acids that may alter drug sensitivity. Inactivation of ibpA did not yield significant tobramycin MIC changes. However, inactivation of two heat shock proteins/proteases ibpA/clpB, ibpA/PA0779, or ibpA/hslV led to increased tobramycin sensitivity changes in P. aeruginosa.

Trimethoprim

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase type 6 (DFRA6) [178]

• Resistant Disease: Proteus mirabilis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Trimethoprim
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain JM101; 83333
• In Vitro Model: Escherichia coli strain k12 JM103; 83333
• In Vitro Model: Proteus mirabilis strain J120; 584
• Experiment for Molecule Alteration: Chain termination method assay
• Mechanism Description: High-level resistance to trimethoprim (Tp) (MIC > 1000 mg/L) is mediated by dihydrofolate reductases (DHFRs) which are resistant to the drug, The gene encoding the type VI DHFR was isolated from P. mirabilis strain J120 (pUk672).

Vancomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA-directed RNA polymerase subunit beta' (RPOC) [112]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.D244Y
• Resistant Drug: Vancomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Clostridioides difficile ATCC 43255; 499175
• In Vitro Model: Clostridioides difficile NB95009; 1496
• In Vitro Model: Clostridioides difficile NB95026; 1496
• In Vitro Model: Clostridioides difficile NB95031; 1496
• In Vitro Model: Clostridioides difficile NB95047; 1496
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: NB95026-JAL0865 had a single mutation encoding a D244Y substitution in the RNA polymerase subunit Beta.Reduced susceptibility to fidaxomicin and vancomycin was associated with mutations mediating target modifications (RNA polymerase and cell wall, respectively), as well as with mutations that may contribute to reduced susceptibility via other mechanisms.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Putative ABC transporter ATP-binding component (OTRC) [28]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vancomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli ET12567 (pUZ8002); 562
• In Vitro Model: Streptomyces rimosus M4018; 1927
• In Vitro Model: Streptomyces rimosus SR16; 1927
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: OtrC is a multidrug resistance protein based on an ATP hydrolysis-dependent active efflux mechanism.OtrC is a multidrug resistance protein based on an ATP hydrolysis-dependent active efflux mechanism.

Zithromax

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: erm(X)cj (Unclear) [82]

• Resistant Disease: Corynebacterium jeikeium infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Frameshift mutation; Codon 216 frame shift
• Resistant Drug: Zithromax
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Corynebacterium diphtheriae isolate; 1717
• In Vitro Model: Corynebacterium glutamicum kO8; 1718
• In Vitro Model: Corynebacterium jeikeium isolates; 38289
• In Vitro Model: Escherichia coli ATCC 25923; 562
• In Vitro Model: Escherichia coli strain XL1-Blue MRF9; 562
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion methods assay; agar dilution methods assay
• Mechanism Description: Abundant amplificationproducts of slightly less than 400 bp were generated from DNAisolated from the 17 MLSb-resistant strains, whereas no am-plification products were generated with the DNA isolatedfrom the three susceptible strains. The DNA sequences of the amplification products showed 95% identity to the erm(X) gene isolated from a C. xerosis strain,erm(X)cx or ermCX. Thus, MLSb resistance in C. jeikeiumis associated with the presence of an allele, erm(X)cj, of the class Xermgenes. The first 215 amino acids of the predicted polypeptides for strains CJ12 and CJ21 are 93.5 and 98.6% identical to Erm(X)cx, the Erm protein from C. xerosi. The major difference between the two Erm(X)cj polypeptides and the Erm(X)cx polypeptide is a frame shift within codon 216. This results in the Erm(X)cj polypeptides being 31 amino acids longer than Erm(X)cx.

Imipenem

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: CATB10-Ib variant (CATB10) [48]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Imipenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa TS-103; 287
• In Vitro Model: Pseudomonas aeruginosa TS-832035; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: P. aeruginosa TS-832035 produces a carbapenemase, coded by a blaVIM-1 determinant carried by the chromosomal class 1 integron In70.2 (containing also the aacA4, aphA15, and aadA1 genes in its cassette array),which induce the resistance to carbapenems.

Key Molecule: Metallo-beta-lactamase (VIM1) [5]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Imipenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: A. xylosoxydans AX22 exhibited broad-spectrum resistance to Beta-lactams and aminoglycosides. The Beta-lactam resistance pattern (including piperacillin, ceftazidime, and carbapenem resistance) was unusual for this species, and the high-level carbapenem resistance suggested the production of an acquired carbapenemase. In fact, carbapenemase activity was detected in a crude extract of AX22 (specific activity, 184 +/- 12 U/mg of protein), and this activity was reduced (>80%) after incubation of the crude extract with 2 mM EDTA, suggesting the presence of a metallo-Beta-lactamase determinant.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Porin D (OPRD) [179], [180], [181]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; c.752insAGTC
• Resistant Drug: Imipenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: P. aeruginosa OprD is a 443-amino-acid protein that facilitates the uptake of basic amino acids, imipenem, and gluconate across the outer membrane.Nucleotide sequence analysis revealed a 4-bp (AGTC) insertion in the oprD gene, resulting in a frameshift in the cognate open reading frame. These isolates became imipenem susceptible when the chromosomal oprD lesion was complemented, indicating that the 4-bp insertion in the oprD gene resulted in imipenem resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Pyruvate decarboxylase 5 (PDC5) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• Resistant Drug: Imipenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Key Molecule: Pyruvate decarboxylase 3 (PDC3) [30], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T97A
• Resistant Drug: Imipenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Clinical Trial Drug(s) 5 drug(s) in total

Pristinamycin IA

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase ermE (ERME) [79], [80], [81]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Pristinamycin IA
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli AS19-RrmA-; 562
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli JC7623; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Methylation of specific nucleotides in rRNA is one of the means by which bacteria achieve resistance to macrolides-lincosamides-streptogramin B (MLSB) and ketolide antibiotics.ErmE dimethylation confers high resistance to all the MLSB and ketolide drugs.

Key Molecule: 23S rRNA (Adenine(2503)-C(8))-methyltransferase ClbA (CIBA) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Pristinamycin IA
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Colibactin polyketide synthase ClbC (CLBC) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Pristinamycin IA
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Ceftolozane sulfate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [42]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Y221H
• Resistant Drug: Ceftolozane sulfate
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli EC13; 562
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: Disk diffusion test assay
• Mechanism Description: The CMY-136 Beta-lactamase, a Y221H point mutant derivative of CMY-2,confers an increased level of resistance to ticarcillin, cefuroxime, cefotaxime, and ceftolozane/tazobactam.

LFF571

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Elongation factor Tu (TUF) [182]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.G260E
• Resistant Drug: LFF571
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Clostridium difficile strain ATCC 43255; 499175
• In Vitro Model: Clostridium difficile strain NB95002; 1496
• In Vitro Model: Clostridium difficile strain NB95026; 1496
• In Vitro Model: Clostridium difficile strain NB95031; 1496
• In Vitro Model: Clostridium difficile strain NB95047; 1496
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Selection on inhibitory concentrations of LFF571 resulted in a substitution at the C. difficile residue analogous to G257 in E. coli EF-Tu.All mutants exhibited tufB mutation G782A, resulting in amino acid substitution G260E; NB95013-JAL0759 harbored the G782A change in both tufA and tufB.

Thiostrepton

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA methyltransferase PikR1 (PIKR1) [131], [132]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Thiostrepton
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli BL21(DE3)pLysS; 866768
• In Vitro Model: Escherichia coli S17-1; 1227813
• In Vitro Model: Streptomyces antibioticus ATCC 11891; 1890
• In Vitro Model: Streptomyces venezuelae ATCC 15439; 54571
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Modification of 23S rRNA, which is the target site for methymycin and its derivatives, by PikR1 and PikR2 is a primary self-resistance mechanism.

Key Molecule: rRNA methyltransferase PikR2 (PIKR2) [131], [132]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Thiostrepton
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli BL21(DE3)pLysS; 866768
• In Vitro Model: Escherichia coli S17-1; 1227813
• In Vitro Model: Streptomyces antibioticus ATCC 11891; 1890
• In Vitro Model: Streptomyces venezuelae ATCC 15439; 54571
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Modification of 23S rRNA, which is the target site for methymycin and its derivatives, by PikR1 and PikR2 is a primary self-resistance mechanism.

Apramycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA methyltransferase PikR1 (PIKR1) [131], [132]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Apramycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli BL21(DE3)pLysS; 866768
• In Vitro Model: Escherichia coli S17-1; 1227813
• In Vitro Model: Streptomyces antibioticus ATCC 11891; 1890
• In Vitro Model: Streptomyces venezuelae ATCC 15439; 54571
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Modification of 23S rRNA, which is the target site for methymycin and its derivatives, by PikR1 and PikR2 is a primary self-resistance mechanism.

Key Molecule: rRNA methyltransferase PikR2 (PIKR2) [131], [132]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Apramycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli BL21(DE3)pLysS; 866768
• In Vitro Model: Escherichia coli S17-1; 1227813
• In Vitro Model: Streptomyces antibioticus ATCC 11891; 1890
• In Vitro Model: Streptomyces venezuelae ATCC 15439; 54571
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Modification of 23S rRNA, which is the target site for methymycin and its derivatives, by PikR1 and PikR2 is a primary self-resistance mechanism.

Key Molecule: 16S rRNA (adenine(1408)-N(1))-methyltransferase (KAMB) [114], [115]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Apramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The 16S ribosomal RNA methyltransferase enzymes that modify nucleosides in the drug binding site to provide self-resistance in aminoglycoside-producing micro-organisms have been proposed to comprise two distinct groups of S-adenosyl-l-methionine (SAM)-dependent RNA enzymes, namely the kgm and kam families.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminocyclitol acetyltransferase ApmA (APMA) [183]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Apramycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• In Vitro Model: Escherichia coli JM101; 562
• In Vitro Model: Staphylococcus aureus ST398; 523796
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The apmA gene coded for a protein of 274 amino acids that was related only distantly to acetyltransferases involved in chloramphenicol or streptogramin A resistance.

Investigative Drug(s) 22 drug(s) in total

Amoxicillin/Clavulanic acid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• Resistant Drug: Amoxicillin/Clavulanic acid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Acinetobacter baumannii CIP70.10; 470
• In Vitro Model: Klebsiella pneumoniae kP3; 1290996
• In Vitro Model: Pseudomonas aeruginosa PU21; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: K. pneumoniae kP3 was resistant to all Beta-lactams, including carbapenems, and expressed the carbapenem-hydrolyzing Beta-lactamase OXA-181, which differs from OXA-48 by four amino acid substitutions. Compared to OXA-48, OXA-181 possessed a very similar hydrolytic profile.

Key Molecule: Beta-lactamase (BLA) [14], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Amoxicillin/Clavulanic acid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli JM101; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Beta-lactamases (Beta-lactamhydrolase, EC 3.5.2.6), responsible for most of the resistance to Beta-lactam antibiotics, are often plasmid mediated.The OXA-1 beta-lactamase gene is part of Tn2603, which is borne on the R plasmid RGN238.

Butirosina

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [116]

• Resistant Disease: Stenotrophomonas maltophilia infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Butirosina
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• Experiment for Molecule Alteration: PCR amplification assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Aph(3')-IIc significantly increases MICs of kanamycin, neomycin, butirosin, and paromomycin when expressed in Escherichia coli. Disruption of aph(3')-IIc results in decreased MICs of these drugs.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [6]

• Resistant Disease: Streptococcus faecalis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Butirosina
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain JM 10; 562
• In Vitro Model: Escherichia coli strain k802; 562
• In Vitro Model: Streptococcus faecnlis strain JHZ-15; 1351
• Experiment for Molecule Alteration: Chemical sequencing method assay
• Experiment for Drug Resistance: Disc sensitivity tests assay
• Mechanism Description: Strain BM2182 was examined for aminoglyco- side-modifying activities. That kanamycin B was modified and tobramycin (3'-deoxykanamycin B) was not, indicates that the 3'-hydroxyl group is the site of phosphorylation. That butirosin, lividomycin A, and amikacin were phosphorylated indicates that the enzyme is APH-III.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [7]

• Resistant Disease: Serratia marcescens infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Butirosina
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Cadmium

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Transport protein (ALL3255) [184]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cadmium
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Anabaena sp. PCC7120; 1167
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Liquid culture assay
• Mechanism Description: PCC7120 a homolog of cadmium resistance-associated protein (CadD) involved in cadmium or heavy metal resistance or not, cloning and heterologous expression analysis of all3255 performed in Escherichia coli BL21 (DE3). Our results revealed that the strain transformed with pGEX-5X-2 + all3255 showed resistant towards not only to cadmium but also other heavy metals such as nickel, copper, zinc, lead and cobalt in addition to arsenic than those of transformed with empty vector (pGEX-5X-2).

Cefoxitin/Clavulanate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [15], [29]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cefoxitin/Clavulanate
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Klebsiella pneumoniae strain HEL-1; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The phenotype of Klebsiella pneumoniae HEL-1 indicates a plasmidic cephamycinase gene (blaCMY-2),which is responsible for cephamycin resistance.

Cefoxitin/Sulbactam

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [15], [29]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cefoxitin/Sulbactam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Klebsiella pneumoniae strain HEL-1; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The phenotype of Klebsiella pneumoniae HEL-1 indicates a plasmidic cephamycinase gene (blaCMY-2),which is responsible for cephamycin resistance.

Cefoxitin/Tazobactam

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [15], [29]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cefoxitin/Tazobactam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Klebsiella pneumoniae strain HEL-1; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The phenotype of Klebsiella pneumoniae HEL-1 indicates a plasmidic cephamycinase gene (blaCMY-2),which is responsible for cephamycin resistance.

Ceftazidime/Cloxacillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: CATB10-Ib variant (CATB10) [48]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ceftazidime/Cloxacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa TS-103; 287
• In Vitro Model: Pseudomonas aeruginosa TS-832035; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: P. aeruginosa TS-832035 produces a carbapenemase, coded by a blaVIM-1 determinant carried by the chromosomal class 1 integron In70.2 (containing also the aacA4, aphA15, and aadA1 genes in its cassette array),which induce the resistance to carbapenems.

Corticostatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Defensin resistance ABC transporter DerAB (DERAB) [185]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Corticostatin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli DH10beta; 316385
• In Vitro Model: Lactococcus lactis MG1363; 1358
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Bce-like systems mediate resistance against antimicrobial peptides in Firmicutes bacteria. Lactobacillus casei BL23 encodes an "orphan" ABC transporter that, based on homology to BceAB-like systems, was proposed to contribute to antimicrobial peptide resistance. The transporter specifically conferred resistance against insect-derived cysteine-stabilized alphabeta defensins, and it was therefore renamed DerAB for defensin resistance ABC trans.

Coumermycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA gyrase subunit B (GYRB) [143]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.R136C+p.R136H+p.R136S+p.G164V
• Resistant Drug: Coumermycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Escherichia coli strain N4177; 562
• In Vitro Model: Escherichia coli strain CC1; 562
• In Vitro Model: Escherichia coli strain CC5; 562
• In Vitro Model: Escherichia coli strain LE234; 562
• In Vitro Model: Escherichia coli strain LE316; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Coumarins are inhibitors of the ATP hydrolysis and DNA supercoiling reactions catalysed by DNA gyrase. four mutations have been identified regaeding conferring coumarin resistance to Escherichia coli: Arg-136 to Cys, His or Ser and Gly-164 to Val.Significant differences in the susceptibility of mutant GyrB proteins to inhibition by either chlorobiocin and novobiocin or coumermycin have been found, suggesting wider contacts between coumermycin and GyrB.

Elfamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Elongation factor Tu (TUF) [186]

• Resistant Disease: Enterococci faecalis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Elfamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus avium strain NCTC9938; 33945
• In Vitro Model: Enterococcus casseliflavus strain NCIMB11449; 37734
• In Vitro Model: Enterococcus durans strain NCTC8174; 53345
• In Vitro Model: Enterococcus faecalis strain NCTC775; 1351
• In Vitro Model: Enterococcus faecium strain NCTC 7171; 1352
• In Vitro Model: Enterococcus gallinarum strain NCTC11428; 1353
• In Vitro Model: Enterococcus hirae strain NCIMB6459; 1354
• In Vitro Model: Enterococcus raffinosus strain NCTC 12192; 1989
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Among enterococci, susceptibility or resistance to elfamycins appears to be determined by the bacterial protein synthesis elongation factor EF-Tu. E.faecium, E.durans, and E.hirae were susceptible to the elfamycins, while isolates of E.faecalis and all other species tested were resistant. Elfamycin resistance in E.faecalis ATCC7080 was mediated by the intrinsic resistance of its EF-Tu.

Key Molecule: Elongation factor Tu (TUF) [186]

• Resistant Disease: Enterococci casseliflavus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Elfamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus avium strain NCTC9938; 33945
• In Vitro Model: Enterococcus casseliflavus strain NCIMB11449; 37734
• In Vitro Model: Enterococcus durans strain NCTC8174; 53345
• In Vitro Model: Enterococcus faecalis strain NCTC775; 1351
• In Vitro Model: Enterococcus faecium strain NCTC 7171; 1352
• In Vitro Model: Enterococcus gallinarum strain NCTC11428; 1353
• In Vitro Model: Enterococcus hirae strain NCIMB6459; 1354
• In Vitro Model: Enterococcus raffinosus strain NCTC 12192; 1989
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Among enterococci, susceptibility or resistance to elfamycins appears to be determined by the bacterial protein synthesis elongation factor EF-Tu. E.faecium, E.durans, and E.hirae were susceptible to the elfamycins, while isolates of E.faecalis and all other species tested were resistant. Elfamycin resistance in E.faecalis ATCC7080 was mediated by the intrinsic resistance of its EF-Tu.

Key Molecule: Elongation factor Tu (TUF) [186]

• Resistant Disease: Enterococci avium infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Elfamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus avium strain NCTC9938; 33945
• In Vitro Model: Enterococcus casseliflavus strain NCIMB11449; 37734
• In Vitro Model: Enterococcus durans strain NCTC8174; 53345
• In Vitro Model: Enterococcus faecalis strain NCTC775; 1351
• In Vitro Model: Enterococcus faecium strain NCTC 7171; 1352
• In Vitro Model: Enterococcus gallinarum strain NCTC11428; 1353
• In Vitro Model: Enterococcus hirae strain NCIMB6459; 1354
• In Vitro Model: Enterococcus raffinosus strain NCTC 12192; 1989
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Among enterococci, susceptibility or resistance to elfamycins appears to be determined by the bacterial protein synthesis elongation factor EF-Tu. E.faecium, E.durans, and E.hirae were susceptible to the elfamycins, while isolates of E.faecalis and all other species tested were resistant. Elfamycin resistance in E.faecalis ATCC7080 was mediated by the intrinsic resistance of its EF-Tu.

Key Molecule: Elongation factor Tu (TUF) [186]

• Resistant Disease: Enterococci raffinosus infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Elfamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus avium strain NCTC9938; 33945
• In Vitro Model: Enterococcus casseliflavus strain NCIMB11449; 37734
• In Vitro Model: Enterococcus durans strain NCTC8174; 53345
• In Vitro Model: Enterococcus faecalis strain NCTC775; 1351
• In Vitro Model: Enterococcus faecium strain NCTC 7171; 1352
• In Vitro Model: Enterococcus gallinarum strain NCTC11428; 1353
• In Vitro Model: Enterococcus hirae strain NCIMB6459; 1354
• In Vitro Model: Enterococcus raffinosus strain NCTC 12192; 1989
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Among enterococci, susceptibility or resistance to elfamycins appears to be determined by the bacterial protein synthesis elongation factor EF-Tu. E.faecium, E.durans, and E.hirae were susceptible to the elfamycins, while isolates of E.faecalis and all other species tested were resistant. Elfamycin resistance in E.faecalis ATCC7080 was mediated by the intrinsic resistance of its EF-Tu.

Key Molecule: Elongation factor Tu (TUF) [186]

• Resistant Disease: Enterococci gallinarum infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Elfamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus avium strain NCTC9938; 33945
• In Vitro Model: Enterococcus casseliflavus strain NCIMB11449; 37734
• In Vitro Model: Enterococcus durans strain NCTC8174; 53345
• In Vitro Model: Enterococcus faecalis strain NCTC775; 1351
• In Vitro Model: Enterococcus faecium strain NCTC 7171; 1352
• In Vitro Model: Enterococcus gallinarum strain NCTC11428; 1353
• In Vitro Model: Enterococcus hirae strain NCIMB6459; 1354
• In Vitro Model: Enterococcus raffinosus strain NCTC 12192; 1989
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Among enterococci, susceptibility or resistance to elfamycins appears to be determined by the bacterial protein synthesis elongation factor EF-Tu. E.faecium, E.durans, and E.hirae were susceptible to the elfamycins, while isolates of E.faecalis and all other species tested were resistant. Elfamycin resistance in E.faecalis ATCC7080 was mediated by the intrinsic resistance of its EF-Tu.

Homidium bromide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein PmpM (PMPM) [1]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Homidium bromide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32/pSTV28; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: PmpM is a multi drug efflux pump coupled with hydrogen ions, which reduces the intracellular drug concentration and produces drug resistance.

Key Molecule: Ethidium resistance protein (EMRE) [187]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Homidium bromide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli pXZL1582; 668369
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Luria-Bertani (LB) broth and agar dilution assay
• Mechanism Description: EmrE can pump out toxic compounds such as methyl viologen and play an important role in the intrinsic resistance of P. aeruginosa to aminoglycosides and cationic dyes.

Key Molecule: Outer membrane protein OprM (OPRM) [187]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Homidium bromide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli pXZL1582; 668369
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Luria-Bertani (LB) broth and agar dilution assay
• Mechanism Description: The MexAB-OprM system, which is the major, constitutively expressed, multidrug efflux pump and the first discovered member of RND family exporter in P. aeruginosa, is known to pump out mostly lipophilic and amphiphilic drugs. MexAB-OprM plays an important role in the intrinsic resistance of P. aeruginosa to aminoglycosides and cationic dyes.

Linopristin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Virginiamycin B lyase (VGBC) [35]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Linopristin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Paenibacillus sp. LC231; 1120679
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Vgb is a streptogramin B lyase and VgbC inactivates linopristin by Beta-elimination.

Lividomycin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [6]

• Resistant Disease: Streptococcus faecalis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Lividomycin A
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain JM 10; 562
• In Vitro Model: Escherichia coli strain k802; 562
• In Vitro Model: Streptococcus faecnlis strain JHZ-15; 1351
• Experiment for Molecule Alteration: Chemical sequencing method assay
• Experiment for Drug Resistance: Disc sensitivity tests assay
• Mechanism Description: Strain BM2182 was examined for aminoglyco- side-modifying activities. That kanamycin B was modified and tobramycin (3'-deoxykanamycin B) was not, indicates that the 3'-hydroxyl group is the site of phosphorylation. That butirosin, lividomycin A, and amikacin were phosphorylated indicates that the enzyme is APH-III.

Midecamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Oleandomycin glycosyltransferase oleD (OLED) [188]

• Resistant Disease: Bacillus intestinalis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Midecamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Bacillus intestinalis strain T30; 1963032
• Experiment for Molecule Alteration: SDS-PAGE analysis
• Experiment for Drug Resistance: Broth microdilution antifungal susceptibility test assay

Key Molecule: Oleandomycin glycosyltransferase oleD (OLED) [188]

• Resistant Disease: Bacillus intestinalis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Q327A
• Resistant Drug: Midecamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Bacillus intestinalis strain T30; 1963032
• Experiment for Molecule Alteration: SDS-PAGE analysis
• Experiment for Drug Resistance: Broth microdilution antifungal susceptibility test assay

Key Molecule: Oleandomycin glycosyltransferase oleD (OLED) [188]

• Resistant Disease: Bacillus intestinalis infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Q327F
• Resistant Drug: Midecamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Bacillus intestinalis strain T30; 1963032
• Experiment for Molecule Alteration: SDS-PAGE analysis
• Experiment for Drug Resistance: Broth microdilution antifungal susceptibility test assay

Moenomycin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette transporter A (ABCA) [95], [96], [97]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Moenomycin A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Staphylococcus aureus MW2; 1242971
• In Vivo Model: Swiss webster male mice model; Mus musculus
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The ATP-dependent transporter gene abcA in Staphylococcus aureus confers resistance to hydrophobic Beta-lactams.

Piperacillin/Tazobactam

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• Resistant Drug: Piperacillin/Tazobactam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Acinetobacter baumannii CIP70.10; 470
• In Vitro Model: Klebsiella pneumoniae kP3; 1290996
• In Vitro Model: Pseudomonas aeruginosa PU21; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: K. pneumoniae kP3 was resistant to all Beta-lactams, including carbapenems, and expressed the carbapenem-hydrolyzing Beta-lactamase OXA-181, which differs from OXA-48 by four amino acid substitutions. Compared to OXA-48, OXA-181 possessed a very similar hydrolytic profile.

Key Molecule: Beta-lactamase (BLA) [14], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Piperacillin/Tazobactam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli JM101; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Beta-lactamases (Beta-lactamhydrolase, EC 3.5.2.6), responsible for most of the resistance to Beta-lactam antibiotics, are often plasmid mediated.The OXA-1 beta-lactamase gene is part of Tn2603, which is borne on the R plasmid RGN238.

Key Molecule: Beta-lactamase (BLA) [44]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.V88L+p.M154L
• Resistant Drug: Piperacillin/Tazobactam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli ST648; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: NDM-5 differed from existing enzymes due to substitutions at positions 88 (Val - Leu) and 154 (Met - Leu) and reduced the susceptibility of Escherichia coli TOP10 transformants to expanded-spectrum cephalosporins and carbapenems when expressed under its native promoter.

Pleuromutilins

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Tiamulin efflux ATP-binding protein (TAEA) [35]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Pleuromutilins
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Paenibacillus sp. LC231; 1120679
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: These new resistance elements are discussed below. We also identified two predicted ABC-transporters that confer resistance to tetracycline (TetAB(48)) and tiamulin (TaeA).

Key Molecule: ABC transporter ATP-binding protein (ABCP) [89], [90]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T450I
• Resistant Drug: Pleuromutilins
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Enterococcus faecium HM1070; 1352
• In Vitro Model: Enterococcus faecium UCN80; 1352
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: ABC systems constitute one of the largest families of proteins, with most of them being involved in import and export, often called ABC transporters.Several of these class 2 ABC systems have been involved in MLS resistance, such as Msr-, Vga-, or Lsa-like proteins.The observed profile of cross-resistance to lincosamides, streptogramins A, and pleuromutilins conferred by Eat(A)v was similar to those conferred by other Lsa-like proteins.

Pristinamycin IIA

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S rRNA (Adenine(2503)-C(8))-methyltransferase ClbA (CIBA) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Pristinamycin IIA
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC superfamily ATP binding cassette transporter (ABCCT) [137], [138]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Pristinamycin IIA
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• In Vitro Model: Staphylococcus saprophyticus ATCC 15305; 342451
• In Vitro Model: Staphylococcus sciuri ATCC 29059; 1296
• In Vitro Model: Staphylococcus sciuri ATCC 29062; 1296
• In Vitro Model: Staphylococcus sciuri ATCC 700058; 1296
• In Vitro Model: Staphylococcus sciuri ATCC 700061; 1296
• In Vitro Model: Staphylococcus sciuri BL2; 1296
• In Vitro Model: Staphylococcus sciuri SS226; 1296
• In Vitro Model: Staphylococcus sciuri SVv1; 1296
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: Efflux-mediated resistance to MLS antibiotics in staphylococci relies on the ATPase activity of a very special kind of ATP-binding cassette (ABC) protein.By whole-genome sequencing of strain ATCC 29059, we identified a candidate gene that encodes an ATP-binding cassette protein similar to the Lsa and VmlR resistance determinants. Isolation and reverse transcription-quantitative PCR (qRT-PCR) expression studies confirmed that Sal(A) can confer a moderate resistance to lincosamides (8 times the MIC of lincomycin) and a high-level resistance to streptogramins A. The chromosomal location of sal(A) between two housekeeping genes of the staphylococcal core genome supports the gene's ancient origins and thus innate resistance to these antimicrobials within S. sciuri subspecies.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Colibactin polyketide synthase ClbC (CLBC) [86]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Pristinamycin IIA
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Quinupristin/Dalfopristin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Ribosomal RNA large subunit methyltransferase (CFR ) [85]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Quinupristin/Dalfopristin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Cfr confers resistance to antibiotics binding to the peptidyl transferase center on the ribosome.The primary product of the Cfr-mediated methylation is 8-methyladenosine (m8A), a new natural RNA modification that has so far not been seen at sites other than A2503 in 23S rRNA.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter ATP-binding protein (ABCP) [89], [90]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.T450I
• Resistant Drug: Quinupristin/Dalfopristin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Enterococcus faecium HM1070; 1352
• In Vitro Model: Enterococcus faecium UCN80; 1352
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: ABC systems constitute one of the largest families of proteins, with most of them being involved in import and export, often called ABC transporters.Several of these class 2 ABC systems have been involved in MLS resistance, such as Msr-, Vga-, or Lsa-like proteins.The observed profile of cross-resistance to lincosamides, streptogramins A, and pleuromutilins conferred by Eat(A)v was similar to those conferred by other Lsa-like proteins.

Sulfisomidine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [189]

• Resistant Disease: Streptococcus pyogenes infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.E9D+p.A37V+p.D39Q+p.H40Q+p.E42D+p.M44L+p.D47G+p.C63Y+p.T69A+p.D73E+p.V78M+p.E84A+p.N85K+p.I88V+p.W115R+p.Q122E+p.F124L+p.A132V+p.D141K+p.E147D+p.G157S+p.N158A+p.L164I+p.K171D+p.A182P+p.Q187H+p.R197H+p.R213G+p.I246L+p.D257E
• Resistant Drug: Sulfisomidine
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptococcus pyogenes strain G1; 1314
• In Vitro Model: Streptococcus pyogenes strain G2; 1314
• In Vitro Model: Streptococcus pyogenes strain G52; 1314
• In Vitro Model: Streptococcus pyogenes strain G56; 1314
• In Vitro Model: Streptococcus pyogenes strain G68; 1314
• In Vitro Model: Streptococcus pyogenes strain G71; 1314
• In Vitro Model: Streptococcus pyogenes strain G72; 1314
• In Vitro Model: Streptococcus pyogenes strain G76; 1314
• Experiment for Molecule Alteration: Dideoxy-chain termination method assay
• Mechanism Description: Sulfonamide resistance in recent isolates of Streptococcus pyogenes was found to be associated with alterations of the chromosomally encoded dihydropteroate synthase (DHPS). There were 111 different nucleotides (13.8%) in the genes found in susceptible and resistant isolates, respectively, resulting in 30 amino acid changes (11.3%).

Key Molecule: Dihydrofolate reductase (DHFR) [189]

• Resistant Disease: Streptococcus pyogenes infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.I8V+p.N11K+p.D39Q+p.H40Q+p.E42D+p.M44L+p.D47G+p.C63Y+p.T69A+p.D73E+p.V78M+p.K80I+p.E84A+p.N85K+p.I88V+p.Q122E+p.F124L+p.A132V+p.D141K+p.E147D+p.G157S+p.N158A+p.L164I+p.K171D+p.Q187H+p.R213G+p.V214I+p.I246L+p.D257E
• Resistant Drug: Sulfisomidine
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptococcus pyogenes strain G1; 1314
• In Vitro Model: Streptococcus pyogenes strain G2; 1314
• In Vitro Model: Streptococcus pyogenes strain G52; 1314
• In Vitro Model: Streptococcus pyogenes strain G56; 1314
• In Vitro Model: Streptococcus pyogenes strain G68; 1314
• In Vitro Model: Streptococcus pyogenes strain G71; 1314
• In Vitro Model: Streptococcus pyogenes strain G72; 1314
• In Vitro Model: Streptococcus pyogenes strain G76; 1314
• Experiment for Molecule Alteration: Dideoxy-chain termination method assay
• Mechanism Description: Sulfonamide resistance in recent isolates of Streptococcus pyogenes was found to be associated with alterations of the chromosomally encoded dihydropteroate synthase (DHPS). There were 111 different nucleotides (13.8%) in the genes found in susceptible and resistant isolates, respectively, resulting in 30 amino acid changes (11.3%).

Tetraphenylphosphonium chloride

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein PmpM (PMPM) [1]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetraphenylphosphonium chloride
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32/pSTV28; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: PmpM is a multi drug efflux pump coupled with hydrogen ions, which reduces the intracellular drug concentration and produces drug resistance.

Ticarcillin/Clavulanic acid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• Resistant Drug: Ticarcillin/Clavulanic acid
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Acinetobacter baumannii CIP70.10; 470
• In Vitro Model: Klebsiella pneumoniae kP3; 1290996
• In Vitro Model: Pseudomonas aeruginosa PU21; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: K. pneumoniae kP3 was resistant to all Beta-lactams, including carbapenems, and expressed the carbapenem-hydrolyzing Beta-lactamase OXA-181, which differs from OXA-48 by four amino acid substitutions. Compared to OXA-48, OXA-181 possessed a very similar hydrolytic profile.

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