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) 38 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) [3]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Acriflavine
• Molecule Alteration: Expression; Inherence
• 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) [4]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amikacin
• Molecule Alteration: Expression; Intergeneric lateral gene transfer
• 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) [5]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amikacin
• Molecule Alteration: Expression; Up-regulation
• 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) [6]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amikacin
• Molecule Alteration: Expression; Inherence
• 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) [7]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amikacin
• Molecule Alteration: Expression; Inherence
• 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) [8]

• Resistant Disease: Streptococcus faecalis infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amikacin
• Molecule Alteration: Expression; Inherence
• 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) [9]

• Resistant Disease: Serratia marcescens infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amikacin
• Molecule Alteration: Expression; Inherence
• 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) [10], [11]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amikacin
• Molecule Alteration: Expression; Inherence
• 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.

Key Molecule: Aminoglycoside N-acetyltransferase AAC(6')-IAP [12]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amikacin
• Molecule Alteration: Expression; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: S. maltophilia JUNP350; N.A.
• Mechanism Description: Compared with vector control,?E. coli?expressing AAC(6')-Iap showed decreased susceptibilities to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin, and tobramycin. Thin-layer chromatography (TLC) analysis revealed that all the aminoglycosides tested, except for apramycin and paromomycin, were acetylated by AAC(6')-Iap. These results indicated that?aac(6')-Iap?is a functional acetyltransferase that modifies the 6'-NH2?position of aminoglycosides and is involved in aminoglycoside resistance.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: TolC family outer membrane protein (TOLC) [13]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amikacin
• Molecule Alteration: Expression; Up-regulation
• 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) [14], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amoxicillin
• Molecule Alteration: Expression; Up-regulation
• 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) [16], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amoxicillin
• Molecule Alteration: Expression; Up-regulation
• 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) [18]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amoxicillin
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• 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) [17], [19]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amoxicillin
• Molecule Alteration: Missense mutation; p.D240G
• 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) [17], [20], [21]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amoxicillin
• Molecule Alteration: Missense mutation; p.D240G
• 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: KBL-1 protein (KBL-1) [12]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Amoxicillin
• Molecule Alteration: Expression; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: S. maltophilia JUNP497; N.A.
• Mechanism Description: Recombinant KBL-1 protein had hydrolytic activities against all the beta-lactams tested, except for aztreonam (Table?3). Recombinant KBL-1 efficiently hydrolyzed the penicillins, including ampicillin, amoxicillin, penicillin G, and piperacillin with?kcat/km?values of 0.422 to 1.166.

Ampicillin

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]
• Resistant Drug: Ampicillin
• Molecule Alteration: Expression; Up-regulation
• 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) [16], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ampicillin
• Molecule Alteration: Expression; Up-regulation
• 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) [17], [22], [23]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ampicillin
• Molecule Alteration: Missense mutation; p.L76N+p.V84I+p.A184V
• 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) [17], [22], [23]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ampicillin
• Molecule Alteration: Missense mutation; p.L76N
• 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) [24]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ampicillin
• Molecule Alteration: Expression; Inherence
• 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) [25]

• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ampicillin
• Molecule Alteration: Expression; Inherence
• 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) [7]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ampicillin
• Molecule Alteration: Expression; Inherence
• 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) [17], [26]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ampicillin
• Molecule Alteration: Missense mutation; p.V77A+p.D114N+p.S140A+p.N288D
• 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) [27]

• Resistant Disease: Enterobacter cloacae infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ampicillin
• Molecule Alteration: Expression; Inherence
• 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.

Key Molecule: KBL-1 protein (KBL-1) [12]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ampicillin
• Molecule Alteration: Expression; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: S. maltophilia JUNP497; N.A.
• Mechanism Description: Recombinant KBL-1 protein had hydrolytic activities against all the beta-lactams tested, except for aztreonam (Table?3). Recombinant KBL-1 efficiently hydrolyzed the penicillins, including ampicillin, amoxicillin, penicillin G, and piperacillin with?kcat/km?values of 0.422 to 1.166.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter ATPase subunit (ABCS) [28], [29], [30]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ampicillin
• Molecule Alteration: Expression; Up-regulation
• 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) [31]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ampicillin
• Molecule Alteration: Expression; Up-regulation
• 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) [4]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Arbekacin
• Molecule Alteration: Expression; Intergeneric lateral gene transfer
• 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) [5]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Arbekacin
• Molecule Alteration: Expression; Up-regulation
• 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 N-acetyltransferase AAC(6')-IAP [12]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Arbekacin
• Molecule Alteration: Expression; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: S. maltophilia JUNP350; N.A.
• Mechanism Description: Compared with vector control,?E. coli?expressing AAC(6')-Iap showed decreased susceptibilities to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin, and tobramycin. Thin-layer chromatography (TLC) analysis revealed that all the aminoglycosides tested, except for apramycin and paromomycin, were acetylated by AAC(6')-Iap. These results indicated that?aac(6')-Iap?is a functional acetyltransferase that modifies the 6'-NH2?position of aminoglycosides and is involved in aminoglycoside resistance.

Key Molecule: Aminoglycoside N-acetyltransferase AAC(6')-IAP [12]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Arbekacin
• Molecule Alteration: Expression; T1080S+V1062L
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Patient-derived S. maltophilia model; Homo sapiens
• Mechanism Description: S. maltophilia?JUNP350 was found to encode a novel 6'-N-aminoglycoside acetyltransferase, AAC(6')-Iap, consisting of 155 amino acids with 85.0% identity to AAC(6')-Iz.?E. coli?transformants expressing?aac(6')-Iap?were less susceptible to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin and tobramycin. The recombinant AAC(6')-Iap protein acetylated all aminoglycosides tested, except for apramycin and paromomycin.

Aztreonam

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

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

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Aztreonam
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• 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) [7]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Aztreonam
• Molecule Alteration: Expression; Inherence
• 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) [17], [26]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Aztreonam
• Molecule Alteration: Missense mutation; p.V77A+p.D114N+p.S140A+p.N288D
• 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: Beta-lactamase (BLA) [17], [32]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Aztreonam
• Molecule Alteration: Expression; Up-regulation
• 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Pyruvate decarboxylase 5 (PDC5) [33], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Aztreonam
• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• 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) [33], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Aztreonam
• Molecule Alteration: Missense mutation; p.T97A
• 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) [34]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Bacitracin A
• Molecule Alteration: Expression; Up-regulation
• 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) [34]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Bacitracin F
• Molecule Alteration: Expression; Up-regulation
• 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) [34]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Bacitracin methylene disalicylate
• Molecule Alteration: Expression; Up-regulation
• 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) [35]

• Resistant Disease: Vibrio alginolyticus infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Balofloxacin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Experiment for Molecule Alteration: Western blot 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) [36]

• Resistant Disease: Enterococcal infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Benzalkonium chloride
• Molecule Alteration: Expression; Up-regulation
• 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) [3]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Benzalkonium chloride
• Molecule Alteration: Expression; Inherence
• 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) [37]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Benzylpenicillin
• Molecule Alteration: Expression; Inherence
• 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.

Key Molecule: KBL-1 protein (KBL-1) [12]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Benzylpenicillin
• Molecule Alteration: Expression; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: S. maltophilia JUNP497; N.A.
• Mechanism Description: Recombinant KBL-1 protein had hydrolytic activities against all the beta-lactams tested, except for aztreonam (Table?3). Recombinant KBL-1 efficiently hydrolyzed the penicillins, including ampicillin, amoxicillin, penicillin G, and piperacillin with?kcat/km?values of 0.422 to 1.166.

Capreomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Capreomycin acetyltransferase (CPAA) [38]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Capreomycin
• Molecule Alteration: Expression; Inherence
• 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) [14], [15]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Carbenicillin
• Molecule Alteration: Expression; Up-regulation
• 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) [13]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Carbenicillin
• Molecule Alteration: Expression; Up-regulation
• 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) [39]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefadroxil
• Molecule Alteration: Expression; Down-regulation
• 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

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Penicillin-binding protein 2C (PBP2C) [1]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefalotin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: jk0412 cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Disk diffusion assay; Microdilution assay; E-Test assay
• Mechanism Description: Six genes encoding putative high molecular weight penicillin-binding proteins (Pbp) are present in the genome of the beta-lactam-resistant strain?Corynebacterium jeikeium?K411. In this study, we show that?pbp2c, one of these six genes, is present in resistant strains of?Corynebacteriaceae?but absent from sensitive strains. The molecular study of the?pbp2c?locus from?C. jeikeium?and its heterologous expression in?Corynebacterium glutamicum?allowed us to show that Pbp2c confers high levels of beta-lactam resistance to the host and is under the control of a beta-lactam-induced regulatory system encoded by two adjacent genes,?jk0410?and?jk0411. The detection of this inducible resistance may require up to 48?h of incubation, particularly in?Corynebacterium amycolatum. Finally, the Pbp3c-expressing strains studied were resistant to all the beta-lactam antibiotics tested, including carbapenems, ceftaroline, and ceftobiprole.

Key Molecule: Penicillin-binding protein 2C (PBP2C) [1]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefalotin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: cu1571 cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Disk diffusion assay; Microdilution assay; E-Test assay
• Mechanism Description: Six genes encoding putative high molecular weight penicillin-binding proteins (Pbp) are present in the genome of the beta-lactam-resistant strain?Corynebacterium jeikeium?K411. In this study, we show that?pbp2c, one of these six genes, is present in resistant strains of?Corynebacteriaceae?but absent from sensitive strains. The molecular study of the?pbp2c?locus from?C. jeikeium?and its heterologous expression in?Corynebacterium glutamicum?allowed us to show that Pbp2c confers high levels of beta-lactam resistance to the host and is under the control of a beta-lactam-induced regulatory system encoded by two adjacent genes,?jk0410?and?jk0411. The detection of this inducible resistance may require up to 48?h of incubation, particularly in?Corynebacterium amycolatum. Finally, the Pbp6c-expressing strains studied were resistant to all the beta-lactam antibiotics tested, including carbapenems, ceftaroline, and ceftobiprole.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [16], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefalotin
• Molecule Alteration: Expression; Up-regulation
• 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) [18]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefalotin
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• 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) [24]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefalotin
• Molecule Alteration: Expression; Inherence
• 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) [19], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefalotin
• Molecule Alteration: Missense mutation; p.D240G
• 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) [17], [20], [21]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefalotin
• Molecule Alteration: Missense mutation; p.D240G
• 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) [37]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefalotin
• Molecule Alteration: Expression; Inherence
• 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) [17], [32]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefametazole
• Molecule Alteration: Expression; Up-regulation
• 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) [40], [41], [42]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefazolin
• Molecule Alteration: Expression; Down-regulation
• 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) [43]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefepime
• Molecule Alteration: Expression; Inherence
• 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) [7]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefepime
• Molecule Alteration: Expression; Inherence
• 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) [33], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefepime
• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• 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) [33], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefepime
• Molecule Alteration: Missense mutation; p.T97A
• 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) [44]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefmetazole
• Molecule Alteration: Expression; Up-regulation
• 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) [45]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefotaxime
• Molecule Alteration: Missense mutation; p.Y221H
• 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) [18]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefotaxime
• Molecule Alteration: Missense mutation; p.Y104A+p.N110D+p.E175Q+p.S179A
• 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) [46]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefotaxime
• Molecule Alteration: Mutantion; p.V231S
• 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) [17], [22], [23]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefotaxime
• Molecule Alteration: Missense mutation; p.V84I+p.A184V
• 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) [17], [20], [21]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefotaxime
• Molecule Alteration: Missense mutation; p.D240G
• 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) [7]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefotaxime
• Molecule Alteration: Expression; Inherence
• 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) [17], [26]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefotaxime
• Molecule Alteration: Missense mutation; p.V77A+p.D114N+p.S140A+p.N288D
• 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) [17], [32]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefotetan
• Molecule Alteration: Expression; Up-regulation
• 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) [47]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefoxitin
• Molecule Alteration: Missense mutation; p.V88L+p.M154L
• 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) [48]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefoxitin
• Molecule Alteration: Expression; Up-regulation
• 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) [46]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefoxitin
• Molecule Alteration: Mutantion; p.V231S
• 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) [17], [26]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefoxitin
• Molecule Alteration: Missense mutation; p.V77A+p.D114N+p.S140A+p.N288D
• 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: Beta-lactamase (BLA) [17], [32]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefoxitin
• Molecule Alteration: Expression; Up-regulation
• 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.

Cefpirome

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [17], [20], [21]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefpirome
• Molecule Alteration: Missense mutation; p.D240G
• 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) [33], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefpirome
• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• 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) [33], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefpirome
• Molecule Alteration: Missense mutation; p.T97A
• 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) [37]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefradine
• Molecule Alteration: Expression; Inherence
• 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.

Cefsulodin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: 16S rRNA adenine dimethyltransferase (KsgA) [2]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefsulodin
• Molecule Alteration: Missense mutation; A1518/1519
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Pseudomonas aeruginosa; 1763
• Experiment for Molecule Alteration: PCR; Southern blot assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: SOD enzymatic activity and SodM protein levels are reduced in the ksgA mutant strain;The absence of ksgA contributes to an altered antibiotic response

Ceftazidime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: TMB-2 metallo-beta-lactamase (BTMB2) [49]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftazidime
• Molecule Alteration: Expression; Inherence
• 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) [50]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftazidime
• Molecule Alteration: Expression; Up-regulation
• 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) [47]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftazidime
• Molecule Alteration: Missense mutation; p.V88L+p.M154L
• 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) [46]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftazidime
• Molecule Alteration: Missense mutation; p.V231S
• 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) [51]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftazidime
• Molecule Alteration: Expression; Up-regulation
• 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) [17], [22], [23]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftazidime
• Molecule Alteration: Missense mutation; p.V84I+p.A184V
• 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) [17], [20], [21]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftazidime
• Molecule Alteration: Missense mutation; p.D240G
• 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) [7]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftazidime
• Molecule Alteration: Expression; Inherence
• 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) [17], [32]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftazidime
• Molecule Alteration: Expression; Up-regulation
• 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Pyruvate decarboxylase 5 (PDC5) [33], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftazidime
• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• 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) [33], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftazidime
• Molecule Alteration: Missense mutation; p.T97A
• 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) [17], [32]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftibuten
• Molecule Alteration: Expression; Up-regulation
• 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) [17], [20], [21]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftriaxone
• Molecule Alteration: Missense mutation; p.D240G
• 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) [52]

• Resistant Disease: Enterobacter cloacae infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftriaxone
• Molecule Alteration: Expression; Inherence
• 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) [13]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ceftriaxone
• Molecule Alteration: Expression; Up-regulation
• 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) [45]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefuroxime
• Molecule Alteration: Missense mutation; p.Y221H
• 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) [24]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefuroxime
• Molecule Alteration: Expression; Inherence
• 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) [19], [17]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cefuroxime
• Molecule Alteration: Missense mutation; p.D240G
• 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) [37]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cephalexin
• Molecule Alteration: Expression; Inherence
• 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) [24]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cephaloridine
• Molecule Alteration: Expression; Inherence
• 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) [40], [41], [42]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cephaloridine
• Molecule Alteration: Expression; Down-regulation
• 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) [37]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cephalosporin C
• Molecule Alteration: Expression; Inherence
• 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) [37]

• Resistant Disease: Rhodobacter sphaeroides infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Cephapirin
• Molecule Alteration: Expression; Inherence
• 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) [53]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [38]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [25]

• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [54]

• Resistant Disease: Enterococcus faecalis infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [55]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [56]

• Resistant Disease: Lactobacillus reuteri infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [57]

• Resistant Disease: Proteus mirabilis infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [58]

• Resistant Disease: Haemophilus influenzae infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [59]

• Resistant Disease: Clostridium perfringens infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [60]

• Resistant Disease: Agvobactevitlm tumefuciens infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [61]

• Resistant Disease: Clostridium butyricum infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [62]

• Resistant Disease: Vibrio anguillarum infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Up-regulation
• 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) [63], [64]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Up-regulation
• 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) [65], [66]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Up-regulation
• 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) [67]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Up-regulation
• 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) [68]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [43]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [69]

• Resistant Disease: Enterobacter aerogenes infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [70]

• Resistant Disease: Rhodococcus erythropolis infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [71]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Up-regulation
• 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) [72]

• Resistant Disease: Enterococci faecium infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [72]

• Resistant Disease: Enterococci faecalisc infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chloramphenicol
• Molecule Alteration: Expression; Inherence
• 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) [73]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chlortetracycline
• Molecule Alteration: Expression; Up-regulation
• 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) [73]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Chlortetracycline
• Molecule Alteration: Expression; Up-regulation
• 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) [74], [75]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.T83I
• 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) [74], [75]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.H83R
• 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) [76]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S83L; p.S80L
• 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) [76]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S83L; p.S80L
• 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) [77]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S463A
• 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) [77]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S464Y
• 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) [77]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S80I
• 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) [78], [79], [80]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S83L
• 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) [78], [79], [80]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S83W
• 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) [78], [79], [80]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.D87N
• 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) [78], [79], [80]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.G81C
• 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) [78], [79], [80]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.A84P
• 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) [78], [79], [80]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.A67S
• 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) [78], [79], [80]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.Q106H
• 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) [81]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.A99G+p.V134I
• 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) [82], [83], [84]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Clarithromycin
• Molecule Alteration: Expression; Up-regulation
• 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.

References

• Ref 1: Exploration of the role of the penicillin binding protein 2c (Pbp2c) in inducible beta-lactam resistance in Corynebacteriaceae. Front Microbiol. 2024 May 9;15:1327723.
• Ref 2: 16S rRNA methyltransferase KsgA contributes to oxidative stress and antibiotic resistance in Pseudomonas aeruginosa. Sci Rep. 2024 Nov 3;14(1):26484.
• Ref 3: An H(+)-coupled multidrug efflux pump, PmpM, a member of the MATE family of transporters, from Pseudomonas aeruginosa. J Bacteriol. 2004 Jan;186(1):262-5. doi: 10.1128/JB.186.1.262-265.2004.
• Ref 4: Acquisition of 16S rRNA methylase gene in Pseudomonas aeruginosa. Lancet. 2003 Dec 6;362(9399):1888-93. doi: 10.1016/S0140-6736(03)14959-8.
• Ref 5: Identification and characterization of a novel aac(6')-Iag associated with the blaIMP-1-integron in a multidrug-resistant Pseudomonas aeruginosa. PLoS One. 2013 Aug 12;8(8):e70557. doi: 10.1371/journal.pone.0070557. eCollection 2013.
• Ref 6: Novel 3-N-aminoglycoside acetyltransferase gene, aac(3)-Ic, from a Pseudomonas aeruginosa integron. Antimicrob Agents Chemother. 2003 May;47(5):1746-8. doi: 10.1128/AAC.47.5.1746-1748.2003.
• Ref 7: In70 of plasmid pAX22, a bla(VIM-1)-containing integron carrying a new aminoglycoside phosphotransferase gene cassette. Antimicrob Agents Chemother. 2001 Apr;45(4):1249-53. doi: 10.1128/AAC.45.4.1249-1253.2001.
• Ref 8: Nucleotide sequence of the Streptococcus faecalis plasmid gene encoding the 3'5"-aminoglycoside phosphotransferase type III. Gene. 1983 Sep;23(3):331-41. doi: 10.1016/0378-1119(83)90022-7.
• Ref 9: Isolation, characterization, and cloning of a plasmid-borne gene encoding a phosphotransferase that confers high-level amikacin resistance in enteric bacilli. Antimicrob Agents Chemother. 1988 Sep;32(9):1379-84. doi: 10.1128/AAC.32.9.1379.
• Ref 10: Cloning and DNA sequence analysis of an aac(3)-Vb gene from Serratia marcescens. Antimicrob Agents Chemother. 1992 Oct;36(10):2222-7. doi: 10.1128/AAC.36.10.2222.
• Ref 11: Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes. Microbiol Rev. 1993 Mar;57(1):138-63. doi: 10.1128/mr.57.1.138-163.1993.
• Ref 12: Stenotrophomonas maltophilia from Nepal Producing Two Novel Antibiotic Inactivating Enzymes, a Class A beta-Lactamase KBL-1 and an Aminoglycoside 6'-N-Acetyltransferase AAC(6')-Iap. Microbiol Spectr. 2022 Aug 31;10(4):e0114322.
• Ref 13: AbuO, a TolC-like outer membrane protein of Acinetobacter baumannii, is involved in antimicrobial and oxidative stress resistance. Antimicrob Agents Chemother. 2015 Feb;59(2):1236-45. doi: 10.1128/AAC.03626-14. Epub 2014 Dec 15.
• Ref 14: Genetic analysis of the beta-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to beta-lactam antibiotics. Microbiology (Reading). 2005 Feb;151(Pt 2):521-532. doi: 10.1099/mic.0.27629-0.
• Ref 15: Purification and properties of the Mycobacterium smegmatis mc(2)155 beta-lactamase. FEMS Microbiol Lett. 1997 Apr 1;149(1):11-5. doi: 10.1016/s0378-1097(97)00041-4.
• Ref 16: Precise insertion of antibiotic resistance determinants into Tn21-like transposons: nucleotide sequence of the OXA-1 beta-lactamase gene. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7378-82. doi: 10.1073/pnas.84.21.7378.
• Ref 17: Identifying novel Beta-lactamase substrate activity through in silico prediction of antimicrobial resistance. Microb Genom. 2021 Jan;7(1):mgen000500. doi: 10.1099/mgen.0.000500.
• Ref 18: Characterization of OXA-181, a carbapenem-hydrolyzing class D beta-lactamase from Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011 Oct;55(10):4896-9. doi: 10.1128/AAC.00481-11. Epub 2011 Jul 18.
• Ref 19: Effect of D240G substitution in a novel ESBL CTX-M-27. J Antimicrob Chemother. 2003 Jul;52(1):29-35. doi: 10.1093/jac/dkg256. Epub 2003 May 29.
• Ref 20: Plasmid-mediated extended-spectrum beta-lactamase (CTX-M-3 like) from India and gene association with insertion sequence ISEcp1. FEMS Microbiol Lett. 2001 Jul 24;201(2):237-41. doi: 10.1111/j.1574-6968.2001.tb10762.x.
• Ref 21: Biochemical analysis of the ceftazidime-hydrolysing extended-spectrum beta-lactamase CTX-M-15 and of its structurally related beta-lactamase CTX-M-3. J Antimicrob Chemother. 2002 Dec;50(6):1031-4. doi: 10.1093/jac/dkf240.
• Ref 22: Natural evolution of TEM-1 Beta-lactamase: experimental reconstruction and clinical relevance. FEMS Microbiol Rev. 2010 Nov;34(6):1015-36. doi: 10.1111/j.1574-6976.2010.00222.x.
• Ref 23: Nucleotide sequence of the ampicillin resistance gene of Escherichia coli plasmid pBR322. Proc Natl Acad Sci U S A. 1978 Aug;75(8):3737-41. doi: 10.1073/pnas.75.8.3737.
• Ref 24: Biochemical characterization of the naturally occurring oxacillinase OXA-50 of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2004 Jun;48(6):2043-8. doi: 10.1128/AAC.48.6.2043-2048.2004.
• Ref 25: New aminoglycoside acetyltransferase gene, aac(3)-Id, in a class 1 integron from a multiresistant strain of Vibrio fluvialis isolated from an infant aged 6 months. J Antimicrob Chemother. 2004 Jun;53(6):947-51. doi: 10.1093/jac/dkh221. Epub 2004 Apr 29.
• Ref 26: Cefotaxime-resistant Enterobacteriaceae isolates from a hospital in Warsaw, Poland: identification of a new CTX-M-3 cefotaxime-hydrolyzing beta-lactamase that is closely related to the CTX-M-1/MEN-1 enzyme. Antimicrob Agents Chemother. 1998 Apr;42(4):827-32. doi: 10.1128/AAC.42.4.827.
• Ref 27: Analysis of a carbapenem-hydrolyzing class A beta-lactamase from Enterobacter cloacae and of its LysR-type regulatory protein. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7693-7. doi: 10.1073/pnas.91.16.7693.
• Ref 28: Macrolide efflux in Streptococcus pneumoniae is mediated by a dual efflux pump (mel and mef) and is erythromycin inducible. Antimicrob Agents Chemother. 2005 Oct;49(10):4203-9. doi: 10.1128/AAC.49.10.4203-4209.2005.
• Ref 29: First report of mefA and msrA/msrB multidrug efflux pumps associated with blaTEM-1 Beta-lactamase in Enterococcus faecalis. Int J Infect Dis. 2012 Feb;16(2):e104-9. doi: 10.1016/j.ijid.2011.09.024. Epub 2011 Dec 1.
• Ref 30: Comparative genomics of IncL/M-type plasmids: evolution by acquisition of resistance genes and insertion sequences. Antimicrob Agents Chemother. 2013 Jan;57(1):674-6. doi: 10.1128/AAC.01086-12. Epub 2012 Oct 31.
• Ref 31: Molecular cloning and functional characterization of an ATP-binding cassette transporter OtrC from Streptomyces rimosus. BMC Biotechnol. 2012 Aug 20;12:52. doi: 10.1186/1472-6750-12-52.
• Ref 32: Characterization of the plasmidic beta-lactamase CMY-2, which is responsible for cephamycin resistance. Antimicrob Agents Chemother. 1996 Jan;40(1):221-4. doi: 10.1128/AAC.40.1.221.
• Ref 33: Extended-spectrum cephalosporinases in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2009 May;53(5):1766-71. doi: 10.1128/AAC.01410-08. Epub 2009 Mar 2.
• Ref 34: Undecaprenyl pyrophosphate phosphatase confers low-level resistance to bacitracin in Enterococcus faecalis. J Antimicrob Chemother. 2013 Jul;68(7):1583-93. doi: 10.1093/jac/dkt048. Epub 2013 Mar 3.
• Ref 35: Downregulation of Na(+)-NQR complex is essential for Vibrio alginolyticus in resistance to balofloxacin .J Proteomics. 2012 May 17;75(9):2638-48. doi: 10.1016/j.jprot.2012.03.006. Epub 2012 Mar 17. 10.1016/j.jprot.2012.03.006
• Ref 36: Involvement, and dissemination, of the enterococcal small multidrug resistance transporter QacZ in resistance to quaternary ammonium compounds. J Antimicrob Chemother. 2011 Feb;66(2):283-6. doi: 10.1093/jac/dkq460. Epub 2010 Dec 8.
• Ref 37: Susceptibility of Rhodobacter sphaeroides to beta-lactam antibiotics: isolation and characterization of a periplasmic beta-lactamase (cephalosporinase). J Bacteriol. 1989 Jan;171(1):308-13. doi: 10.1128/jb.171.1.308-313.1989.
• Ref 38: A diverse intrinsic antibiotic resistome from a cave bacterium. Nat Commun. 2016 Dec 8;7:13803. doi: 10.1038/ncomms13803.
• Ref 39: Characterization of the Human Intestinal Drug Transport with Ussing Chamber System Incorporating Freshly Isolated Human Jejunum. Drug Metab Dispos. 2021 Jan;49(1):84-93. doi: 10.1124/dmd.120.000138. Epub 2020 Oct 21.
• Ref 40: Antibiotic stress, genetic response and altered permeability of E. coli. PLoS One. 2007 Apr 11;2(4):e365. doi: 10.1371/journal.pone.0000365.
• Ref 41: Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin Microbiol Rev. 2012 Oct;25(4):661-81. doi: 10.1128/CMR.00043-12.
• Ref 42: Role of porin proteins OmpF and OmpC in the permeation of beta-lactams. Antimicrob Agents Chemother. 1982 Dec;22(6):942-8. doi: 10.1128/AAC.22.6.942.
• Ref 43: Oxacillinase-mediated resistance to cefepime and susceptibility to ceftazidime in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2001 Jun;45(6):1615-20. doi: 10.1128/AAC.45.6.1615-1620.2001.
• Ref 44: Regulation of the expression of the Beta-lactam antibiotic-resistance determinants in methicillin-resistant Staphylococcus aureus (MRSA). Biochemistry. 2014 Mar 18;53(10):1548-50. doi: 10.1021/bi500074w. Epub 2014 Mar 3.
• Ref 45: Genetic, Biochemical, and Structural Characterization of CMY-136 Beta-Lactamase, a Peculiar CMY-2 Variant. ACS Infect Dis. 2019 Apr 12;5(4):528-538. doi: 10.1021/acsinfecdis.8b00240. Epub 2019 Mar 7.
• Ref 46: CMY-42, a novel plasmid-mediated CMY-2 variant AmpC beta-lactamase. Microb Drug Resist. 2011 Jun;17(2):165-9. doi: 10.1089/mdr.2010.0137. Epub 2011 Mar 9.
• Ref 47: A novel variant, NDM-5, of the New Delhi metallo-Beta-lactamase in a multidrug-resistant Escherichia coli ST648 isolate recovered from a patient in the United Kingdom. Antimicrob Agents Chemother. 2011 Dec;55(12):5952-4. doi: 10.1128/AAC.05108-11. Epub 2011 Sep 19.
• Ref 48: Detection of staphylococcal cassette chromosome mec type XI carrying highly divergent mecA, mecI, mecR1, blaZ, and ccr genes in human clinical isolates of clonal complex 130 methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2011 Aug;55(8):3765-73. doi: 10.1128/AAC.00187-11. Epub 2011 Jun 2.
• Ref 49: Detection of tripoli metallo-Beta-lactamase 2 (TMB-2), a variant of blaTMB-1, in clinical isolates of Acinetobacter spp. in Japan. J Antimicrob Chemother. 2013 Jun;68(6):1441-2. doi: 10.1093/jac/dkt031. Epub 2013 Feb 6.
• Ref 50: Genetic and biochemical characterization of a novel metallo-Beta-lactamase, TMB-1, from an Achromobacter xylosoxidans strain isolated in Tripoli, Libya. Antimicrob Agents Chemother. 2012 May;56(5):2241-5. doi: 10.1128/AAC.05640-11. Epub 2012 Jan 30.
• Ref 51: Metallo-Beta-lactamase expression confers an advantage to Pseudomonas aeruginosa isolates compared with other Beta-lactam resistance mechanisms, favoring the prevalence of metallo-Beta-lactamase producers in a clinical environment. Microb Drug Resist. 2010 Sep;16(3):223-30. doi: 10.1089/mdr.2010.0016.
• Ref 52: Survey and molecular genetics of SHV beta-lactamases in Enterobacteriaceae in Switzerland: two novel enzymes, SHV-11 and SHV-12. Antimicrob Agents Chemother. 1997 May;41(5):943-9. doi: 10.1128/AAC.41.5.943.
• Ref 53: The complex resistomes of Paenibacillaceae reflect diverse antibiotic chemical ecologies. ISME J. 2018 Mar;12(3):885-897. doi: 10.1038/s41396-017-0017-5. Epub 2017 Dec 19.
• Ref 54: Sequence of the 50-kb conjugative multiresistance plasmid pRE25 from Enterococcus faecalis RE25. Plasmid. 2001 Nov;46(3):170-87. doi: 10.1006/plas.2001.1544.
• Ref 55: Structure of In31, a blaIMP-containing Pseudomonas aeruginosa integron phyletically related to In5, which carries an unusual array of gene cassettes. Antimicrob Agents Chemother. 1999 Apr;43(4):890-901. doi: 10.1128/AAC.43.4.890.
• Ref 56: Molecular characterization of a plasmid-borne (pTC82) chloramphenicol resistance determinant (cat-TC) from Lactobacillus reuteri G4. Plasmid. 1996 Sep;36(2):116-24. doi: 10.1006/plas.1996.0039.
• Ref 57: Nucleotide sequence analysis of the cat gene of Proteus mirabilis: comparison with the type I (Tn9) cat gene. J Bacteriol. 1985 Oct;164(1):123-9. doi: 10.1128/jb.164.1.123-129.1985.
• Ref 58: Nucleotide sequences of genes encoding the type II chloramphenicol acetyltransferases of Escherichia coli and Haemophilus influenzae, which are sensitive to inhibition by thiol-reactive reagents. Biochem J. 1990 Dec 1;272(2):505-10. doi: 10.1042/bj2720505.
• Ref 59: Relationship between the Clostridium perfringens catQ gene product and chloramphenicol acetyltransferases from other bacteria. Antimicrob Agents Chemother. 1991 Mar;35(3):471-6. doi: 10.1128/AAC.35.3.471.
• Ref 60: Nucleotide sequence analysis of a chloramphenicol-resistance determinant from Agrobacterium tumefaciens and identification of its gene product. Gene. 1991 Feb 1;98(1):113-6. doi: 10.1016/0378-1119(91)90112-o.
• Ref 61: Comparative sequence analysis of the catB gene from Clostridium butyricum. Antimicrob Agents Chemother. 1992 Nov;36(11):2548-51. doi: 10.1128/AAC.36.11.2548.
• Ref 62: Cloning and nucleotide sequence analysis of a chloramphenicol acetyltransferase gene from Vibrio anguillarum. Microbiol Immunol. 1992;36(7):695-705. doi: 10.1111/j.1348-0421.1992.tb02072.x.
• Ref 63: Substrate-bound structure of the E. coli multidrug resistance transporter MdfA. Cell Res. 2015 Sep;25(9):1060-73. doi: 10.1038/cr.2015.94. Epub 2015 Aug 4.
• Ref 64: The Escherichia coli cmlA gene encodes the multidrug efflux pump Cmr/MdfA and is responsible for isopropyl-beta-D-thiogalactopyranoside exclusion and spectinomycin sensitivity. J Bacteriol. 1998 Nov;180(22):6072-5. doi: 10.1128/JB.180.22.6072-6075.1998.
• Ref 65: Multifocal outbreaks of metallo-beta-lactamase-producing Pseudomonas aeruginosa resistant to broad-spectrum beta-lactams, including carbapenems. Antimicrob Agents Chemother. 1996 Feb;40(2):349-53. doi: 10.1128/AAC.40.2.349.
• Ref 66: Corynebacterium striatum chloramphenicol resistance transposon Tn5564: genetic organization and transposition in Corynebacterium glutamicum. Plasmid. 1998 Sep;40(2):126-39. doi: 10.1006/plas.1998.1362.
• Ref 67: Characterization of poxtA, a novel phenicol-oxazolidinone-tetracycline resistance gene from an MRSA of clinical origin. J Antimicrob Chemother. 2018 Jul 1;73(7):1763-1769. doi: 10.1093/jac/dky088.
• Ref 68: Novel florfenicol and chloramphenicol resistance gene discovered in Alaskan soil by using functional metagenomics. Appl Environ Microbiol. 2010 Aug;76(15):5321-6. doi: 10.1128/AEM.00323-10. Epub 2010 Jun 11.
• Ref 69: Characterization of In40 of Enterobacter aerogenes BM2688, a class 1 integron with two new gene cassettes, cmlA2 and qacF. Antimicrob Agents Chemother. 1998 Oct;42(10):2557-63. doi: 10.1128/AAC.42.10.2557.
• Ref 70: Transposition of the IS21-related element IS1415 in Rhodococcus erythropolis. J Bacteriol. 1997 Jul;179(14):4635-8. doi: 10.1128/jb.179.14.4635-4638.1997.
• Ref 71: The plasmid-encoded chloramphenicol-resistance protein of Rhodococcus fascians is homologous to the transmembrane tetracycline efflux proteins. Mol Microbiol. 1992 Aug;6(16):2377-85. doi: 10.1111/j.1365-2958.1992.tb01412.x.
• Ref 72: Study of heterogeneity of chloramphenicol acetyltransferase (CAT) genes in streptococci and enterococci by polymerase chain reaction: characterization of a new CAT determinant. Antimicrob Agents Chemother. 1993 Dec;37(12):2593-8. doi: 10.1128/AAC.37.12.2593.
• Ref 73: Diversity of the Tetracycline Mobilome within a Chinese Pig Manure Sample. Appl Environ Microbiol. 2016 Oct 14;82(21):6454-6462. doi: 10.1128/AEM.01754-16. Print 2016 Nov 1.
• Ref 74: gyrA and parC mutations in quinolone-resistant clinical isolates of Pseudomonas aeruginosa from Nini Hospital in north Lebanon. J Infect Chemother. 2013 Feb;19(1):77-81. doi: 10.1007/s10156-012-0455-y. Epub 2012 Jul 21.
• Ref 75: DNA gyrase gyrA mutations in quinolone-resistant clinical isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1995 Sep;39(9):1970-2. doi: 10.1128/AAC.39.9.1970.
• Ref 76: [Investigation of fluoroquinolone resistance mechanisms in clinical Acinetobacter baumannii isolates]. Mikrobiyol Bul. 2016 Apr;50(2):278-86. doi: 10.5578/mb.24126.
• Ref 77: Type II and type IV topoisomerase mutations in clinical isolates of Morganella morganii harbouring the qnrD gene. Ann Clin Microbiol Antimicrob. 2014 Aug 9;13:34. doi: 10.1186/s12941-014-0034-4.
• Ref 78: 4-Quinolone resistance mutations in the DNA gyrase of Escherichia coli clinical isolates identified by using the polymerase chain reaction. Antimicrob Agents Chemother. 1991 Feb;35(2):387-9. doi: 10.1128/AAC.35.2.387.
• Ref 79: Quinolone resistance-determining region in the DNA gyrase gyrA gene of Escherichia coli. Antimicrob Agents Chemother. 1990 Jun;34(6):1271-2. doi: 10.1128/AAC.34.6.1271.
• Ref 80: Cloning and characterization of a DNA gyrase A gene from Escherichia coli that confers clinical resistance to 4-quinolones. Antimicrob Agents Chemother. 1989 Jun;33(6):886-94. doi: 10.1128/AAC.33.6.886.
• Ref 81: Plasmid-mediated quinolone resistance pump QepA2 in an Escherichia coli isolate from France. Antimicrob Agents Chemother. 2008 Oct;52(10):3801-4. doi: 10.1128/AAC.00638-08. Epub 2008 Jul 21.
• Ref 82: Activity of the ketolide telithromycin is refractory to Erm monomethylation of bacterial rRNA. Antimicrob Agents Chemother. 2002 Jun;46(6):1629-33. doi: 10.1128/AAC.46.6.1629-1633.2002.
• Ref 83: Expression of the macrolide-lincosamide-streptogramin-B-resistance methylase gene, ermE, from Streptomyces erythraeus in Escherichia coli results in N6-monomethylation and N6,N6-dimethylation of ribosomal RNA. Gene. 1987;55(2-3):319-25. doi: 10.1016/0378-1119(87)90291-5.
• Ref 84: Domain V of 23S rRNA contains all the structural elements necessary for recognition by the ErmE methyltransferase. J Bacteriol. 1994 Nov;176(22):6999-7004. doi: 10.1128/jb.176.22.6999-7004.1994.