Drug Information

Drug (ID: DG00308) and It's Reported Resistant Information

• Name: Ampicillin
• Synonyms: ABPC; Acillin; Adobacillin; Alpen; Amblosin; Amcill; Amfipen; Aminobenzylpenicillin; Ampen; Ampichel; Ampicil; Ampicilina; Ampicillanyl; Ampicillina; Ampicilline; Ampicillinum; Ampicin; Ampifarm; Ampikel; Ampimed; Ampipenin; Ampiscel; Ampisyn; Ampivax; Ampivet; Amplacilina; Amplin; Amplipenyl; Amplisom; Amplital; Austrapen; Binotal; Bonapicillin; Britacil; Campicillin; Cimex; Copharcilin; Delcillin; Deripen; Divercillin; Doktacillin; Duphacillin; Grampenil; Guicitrina; Guicitrine; Lifeampil; Morepen; Norobrittin; Nuvapen; Omnipen; Orbicilina; Penbristol; Penbritin; Penbrock; Penicline; Penimic; Pensyn; Pentrex; Pentrexl; Pentrexyl; Polycillin; Ponecil; Princillin; Principen; QIDamp; Racenacillin; Rosampline;Roscillin; Semicillin; Servicillin; Sumipanto; Supen; Synpenin; Texcillin; Tokiocillin; Tolomol; Totacillin; Totalciclina; Totapen; Trifacilina; Ukapen; Ultrabion; Ultrabron; Vampen; Viccillin; Wypicil; Amfipen V; Amipenix S; Ampicillin A; Ampicillin Anhydrous; Ampicillin Base; Ampicillin acid; Ampicillin anhydrate; Ampicillina [DCIT]; Anhydrous ampicillin; Olin Kid; Pen A; Pen A Oral; Pen Ampil;Penbritin paediatric; Penbritin syrup; Pfizerpen A; Semicillin R; Viccillin S; AY 6108; BA 7305; BRL 1341; Bayer 5427; HI 63; P 50; Principen 125; Principen 250; Principen 500; SQ 17382; AB-PC; AB-PCSol; AY-6108; Ambidrin (TN); Ampi-Co; Ampi-Tab; Ampi-bol; Ampicilina [INN-Spanish]; Ampicilline [INN-French]; Ampicillinum [INN-Latin]; Ampipenin, nt3; Ampy-Penyl; Anhydrous ampicillin (JP15); BRL-1341; D-Ampicillin; D-Cillin; KS-R1; Novo-ampicillin; OMNIPEN (AMPICILLIN); Omnipen (TN); Omnipen-N; P-50; Penbritin-S; Penicillin, Aminobenzyl; Pfizerpen-A; Polycillin-N; Polyflex (Veterinary); Ro-Ampen; SK-Ampicillin; Totacillin (sodium); Totacillin-N; WY-5103; Ampicillin (USP/INN); AMPICILLIN (SEE ALSO AMPICILLIN TRIHYDRATE 7177-48-2); Ampicillin [USAN:BAN:INN:JAN]; Ampicillin [USAN:INN:BAN:JAN];D-(-)-Ampicillin; D-(-)-alpha-Aminobenzylpenicillin; D-(-)-alpha-Aminopenicillin; D-(-)-6-(alpha-Aminophenylacetamido)penicillanic acid; 6-(D(-)-alpha-Aminophenylacetamido)penicillanic acid; 6beta-[(2R)-2-amino-2-phenylacetamido]-2,2-dimethylpenam-3alpha-carbonyl; 6beta-[(2R)-2-amino-2-phenylacetamido]-2,2-dimethylpenam-3alpha-carboxylic acid
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (11 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [3]
  Cholera [ICD-11: 1A00]; [5]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [3]
  Non-tuberculous mycobacteria infection [ICD-11: 1B21]; [7]
  Peritonitis [ICD-11: DC50]; [8]
  Pharyngitis [ICD-11: CA02]; [9]
  Pneumonia [ICD-11: CA40]; [10]
  Shigellosis [ICD-11: 1A02]; [11]
  Tissue pyogenic bacterial infection [ICD-11: 1B7Y]; [12]
  Ulcer [ICD-11: EH90]; [7]
  Urinary tract infection [ICD-11: GC08]; [13]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [4]
  Mycobacterial diseases [ICD-11: 1B2Z ]; [6]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (2 diseases)
  Escherichia coli intestinal infection [ICD-11: 1A03]; [14]
  Periodontal disease [ICD-11: DA0C]; [15]
• Target: Bacterial Penicillin binding protein (Bact PBP); NOUNIPROTAC; [1]
• Formula: C16H19N3O4S
• IsoSMILES: CC1([C@@H](N2[C@H](S1)[C@@H](C2=O)NC(=O)[C@@H](C3=CC=CC=C3)N)C(=O)O)C
• InChI: 1S/C16H19N3O4S/c1-16(2)11(15(22)23)19-13(21)10(14(19)24-16)18-12(20)9(17)8-6-4-3-5-7-8/h3-7,9-11,14H,17H2,1-2H3,(H,18,20)(H,22,23)/t9-,10-,11+,14-/m1/s1
• InChIKey: AVKUERGKIZMTKX-NJBDSQKTSA-N
• PubChem CID: 6249
• ChEBI ID: CHEBI:28971
• TTD Drug ID: D0YA9Z
• VARIDT ID: DR00712
• INTEDE ID: DR2177
• DrugBank ID: DB00415

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Cholera [ICD-11: 1A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Erythromycin esterase (EREA2) [5]

• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae PG153/1; 666
• In Vitro Model: Vibrio cholerae PG170; 666
• In Vitro Model: Vibrio cholerae PL96; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of dfrA5, ereA2 lead to drug resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [5]

• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae O26 strain AS482; 567107
• In Vitro Model: Vibrio cholerae O39 strain AS634; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of aadA1-S lead to drug resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [5]

• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae O62 strain AS438; 666
• In Vitro Model: Vibrio cholerae PG149a; 666
• In Vitro Model: Vibrio cholerae PG224; 666
• In Vitro Model: Vibrio cholerae PG262(b); 666
• In Vitro Model: Vibrio cholerae PG9; 666
• In Vitro Model: Vibrio cholerae PG95; 666
• In Vitro Model: Vibrio cholerae PL1; 666
• In Vitro Model: Vibrio cholerae PL61; 666
• In Vitro Model: Vibrio cholerae PL78/6; 666
• In Vitro Model: Vibrio cholerae PL91; 666
• In Vitro Model: Vibrio cholerae PG92; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of dfrA1 lead to drug resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [5]

• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae PG153/1; 666
• In Vitro Model: Vibrio cholerae PG170; 666
• In Vitro Model: Vibrio cholerae PL96; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of dfrA15 lead to drug resistance.

Bacterial infection [ICD-11: 1A00-1C4Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [1], [2]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• 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]
• 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], [18], [19]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• 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], [18], [19]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• 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) [20]

• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• 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) [21]

• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• 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) [3]

• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• 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], [22]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• 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) [23]

• Resistant Disease: Enterobacter cloacae infection [ICD-11: 1A00-1C4Z]
• 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) [4]

• Resistant Disease: Lactobacillus casei infection [ICD-11: 1A00-1C4Z]
• 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) [24], [25], [26]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• 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) [27]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• 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.

Escherichia coli intestinal infection [ICD-11: 1A03]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [28]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli Co227; 562
• In Vitro Model: Escherichia coli Co228; 562
• In Vitro Model: Escherichia coli Co356; 562
• Experiment for Molecule Alteration: PCR; PCR-restriction fragment length polymorphism analysis; Sequencing assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Multiple-antibiotic-resistant phenotype is associated with gene mutation and mar locus regulation.

Key Molecule: Beta-lactamase (BLA) [28]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli Co227; 562
• In Vitro Model: Escherichia coli Co228; 562
• In Vitro Model: Escherichia coli Co356; 562
• Experiment for Molecule Alteration: PCR; PCR-restriction fragment length polymorphism analysis; Sequencing assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Multiple-antibiotic-resistant phenotype is associated with gene mutation and mar locus regulation.

Key Molecule: Metallo-beta-lactamase (VIM1) [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• 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: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

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

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain JC2926; 562
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: SHV Beta-lactamases confer resistance to a broad spectrum of Beta-lactam antibiotics and are of great therapeutic concern for infections caused by many species of the family Enterobacteriaceae. SHV-1, the original member of the SHV Beta-lactamase family, is present in most strains of Klebsiella pneumoniae and may be either chromosomally or plasmid mediated. A plasmid-mediated SHV-1 is also commonly found in Escherichia coli and is seen in other genera as well.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [29]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli strain JM103; 83333
• In Vitro Model: Bacillus circulans strain; 1397
• In Vitro Model: Streptomyces lividans strain 66; 1200984
• In Vitro Model: Streptomyces lividans strain M180; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Semi-quantitative phosphocellulose-paper binding assay method assay
• Mechanism Description: The previous demonstration that the APH gene of B. circulans could be expressed in E.coli. These contained a 5.5kb Hind3-digest insert (pCH4) or a 2.7kb Sal1-digest insert (pCH5) at the corresponding site in pBR322. Both these derivatives expressed ampicillin and ribostamycin resistance in E.coli.

Non-tuberculous mycobacteria infection [ICD-11: 1B21]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: OXA-23 carbapenemase (BLA OXA-23) [30]

• Resistant Disease: Cutaneous bacterial infection [ICD-11: 1B21.4]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii isolates; 470
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Broth microdilution method assay; Agar dilution method assay
• Mechanism Description: The isolate was resistant to antibiotics other than ampicillin-sulbactam and colistin, suggesting drug resistance due to carbapenemase production by OXA-23.carbapenem resistance in the isolated carbapenem-resistant A. baumannii strain was at least partially conferred by bla OXA-23-like carbapenemase.

Mycobacterial diseases [ICD-11: 1B2Z ]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: P-type ATPase zinc transporter Rv3270 [6]

• Resistant Disease: Bone infection [ICD-11: 1B2Z.9]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: E. coli XL1-Blue; 562
• In Vitro Model: E. coli CS109; 562
• In Vitro Model: M. smegmatis MC2 158; 1772
• Experiment for Molecule Alteration: Gene expression analysis
• Experiment for Drug Resistance: Antimicrobial susceptibility assay; Intracellular drug accumulation activity assay
• Mechanism Description: Metal homeostasis is maintained by the uptake, storage and efflux of metal ions that are necessary for the survival of the bacterium. Homeostasis is mostly regulated by a group of transporters categorized as ABC transporters and P-type ATPases. On the other hand, efflux pumps often play a role in drug-metal cross-resistance. Here, with the help of antibiotic sensitivity, antibiotic/dye accumulation and semi-quantitative biofilm formation assessments we report the ability of Rv3270, a P-type ATPase known for its role in combating Mn2+ and Zn2+ metal ion toxicity in Mycobacterium tuberculosis, in influencing the extrusion of multiple structurally unrelated drugs and enhancing the biofilm formation of Escherichia coli and Mycobacterium smegmatis. Overexpression of Rv3270 increased the tolerance of host cells to norfloxacin, ofloxacin, sparfloxacin, ampicillin, oxacillin, amikacin and isoniazid. A significantly lower accumulation of norfloxacin, ethidium bromide, bocillin FL and levofloxacin in cells harbouring Rv3270 as compared to host cells indicated its role in enhancing efflux activity. Although over-expression of Rv3270 did not alter the susceptibility levels of levofloxacin, rifampicin and apramycin, the presence of a sub-inhibitory concentration of Zn2+ resulted in low-level tolerance towards these drugs. Of note, the expression of Rv3270 enhanced the biofilm-forming ability of the host cells strengthening its role in antimicrobial resistance. Therefore, the study indicated that the over-expression of Rv3270 enhances the drug efflux activity of the micro-organism where zinc might facilitate drug-metal cross-resistance for some antibiotics.

Tissue pyogenic bacterial infection [ICD-11: 1B7Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [12]

• Resistant Disease: Staphylococcus infection [ICD-11: 1B7Y.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Klebsiella pneumoniae isolates; 573
• In Vitro Model: Acinetobacter isolates; 469
• In Vitro Model: Enterobacter cloacae isolates; 550
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: Up-regulation of P-glycoprotein led to ampicillin resistance in the staphylococcus infection.

ICD-13: Digestive system diseases

Periodontal disease [ICD-11: DA0C]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (Q9X4S7) [15]

• Resistant Disease: Chronic periodontitis [ICD-11: DA0C.Y]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Prevotella nigrescens strain; 28133
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: Disc diffusion test
• Mechanism Description: Seventy five percent of patients carried two species of beta-lactamase-producing anaerobic bacteria that comprised 9.4% of the total number of cultivable bacteria. Fifty one percent of beta-lactamase-producing strains mainly Prevotella, Porphyromonas, and Bacteroides carried the cfxA gene, whereas none of them carried blaTEM. Further characterization of the cfxA gene showed that 76.7% of these strains carried the cfxA2 gene, 14% carried cfxA3, and 9.3% carried cfxA6. The cfxA6 gene was present in three Prevotella spp. and in one Porphyromonas spp. Strains containing cfxA genes (56%) were resistant to the beta-lactam antibiotics.

Key Molecule: Beta-lactamase (Q9X4S7) [15]

• Resistant Disease: Chronic periodontitis [ICD-11: DA0C.Y]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Porphyromonas gingivalis strain; 837
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: Disc diffusion test
• Mechanism Description: Seventy five percent of patients carried two species of beta-lactamase-producing anaerobic bacteria that comprised 9.4% of the total number of cultivable bacteria. Fifty one percent of beta-lactamase-producing strains mainly Prevotella, Porphyromonas, and Bacteroides carried the cfxA gene, whereas none of them carried blaTEM. Further characterization of the cfxA gene showed that 76.7% of these strains carried the cfxA2 gene, 14% carried cfxA3, and 9.3% carried cfxA6. The cfxA6 gene was present in three Prevotella spp. and in one Porphyromonas spp. Strains containing cfxA genes (56%) were resistant to the beta-lactam antibiotics.

ICD-16: Genitourinary system diseases

Urinary tract infection [ICD-11: GC08]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [13]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [13]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [13]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Dihydrofolate reductase (DHFR) [13]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

References

• Ref 1: 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 2: 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 3: 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 4: 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 5: Occurrence of antibiotic resistance gene cassettes aac(6')-Ib, dfrA5, dfrA12, and ereA2 in class I integrons in non-O1, non-O139 Vibrio cholerae strains in India. Antimicrob Agents Chemother. 2002 Sep;46(9):2948-55. doi: 10.1128/AAC.46.9.2948-2955.2002.
• Ref 6: P-type ATPase zinc transporter Rv3270 of Mycobacterium tuberculosis enhances multi-drug efflux activity. Microbiology (Reading). 2024 Feb;170(2):001441.
• Ref 7: Investigation and analysis of the characteristics and drug sensitivity of bacteria in skin ulcer infections .Chin J Traumatol. 2017 Aug;20(4):194-197. doi: 10.1016/j.cjtee.2016.09.005. Epub 2017 May 24. 10.1016/j.cjtee.2016.09.005
• Ref 8: Emerging Gram-positive bacteria and drug resistance in cirrhosis patients with spontaneous bacterial peritonitis: A retrospective studyExp Ther Med. 2019 Jun;17(6):4568-4576. doi: 10.3892/etm.2019.7502. Epub 2019 Apr 18.
• Ref 9: Shotgun whole genome sequencing of drug-resistance Streptococcus anginosus strain 47S1 isolated from a patient with pharyngitis in Saudi ArabiaJ Infect Public Health. 2021 Dec;14(12):1740-1749. doi: 10.1016/j.jiph.2021.11.010. Epub 2021 Nov 16.
• Ref 10: Analysis of clinical distribution and drug resistance of klebsiella pneumoniae pulmonary infection in patients with hypertensive intra cerebral hemorrhage after minimally invasive surgeryPak J Med Sci. 2022 Jan-Feb;38(1):237-242. doi: 10.12669/pjms.38.1.4439.
• Ref 11: Update on Shigella and Nontyphoidal Salmonella Antimicrobial Drug Resistance: Implications on Empirical Treatment of Acute Infectious Diarrhea in CambodiaAntimicrob Agents Chemother. 2021 Oct 18;65(11):e0067121. doi: 10.1128/AAC.00671-21. Epub 2021 Aug 16.
• Ref 12: Pathogen characteristics reveal novel antibacterial approaches for interstitial lung disease .Pulm Pharmacol Ther. 2014 Dec;29(2):250-4. doi: 10.1016/j.pupt.2014.03.005. Epub 2014 Apr 1. 10.1016/j.pupt.2014.03.005
• Ref 13: Global spread of mobile antimicrobial drug resistance determinants in human and animal Escherichia coli and Salmonella strains causing community-acquired infections. Clin Infect Dis. 2009 Aug 1;49(3):365-71. doi: 10.1086/600301.
• Ref 14: Automated thermal cycling is superior to traditional methods for nucleotide sequencing of bla(SHV) genes. Antimicrob Agents Chemother. 1999 Dec;43(12):2960-3. doi: 10.1128/AAC.43.12.2960.
• Ref 15: Detection of cfxA2, cfxA3, and cfxA6 genes in beta-lactamase producing oral anaerobes .J Appl Oral Sci. 2016 Apr;24(2):142-7. doi: 10.1590/1678-775720150469. 10.1590/1678-775720150469
• 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: 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 19: 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 20: 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 21: 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 22: 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 23: 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 24: 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 25: 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 26: 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 27: 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 28: Mechanisms of resistance in multiple-antibiotic-resistant Escherichia coli strains of human, animal, and food origins. Antimicrob Agents Chemother. 2004 Oct;48(10):3996-4001. doi: 10.1128/AAC.48.10.3996-4001.2004.
• Ref 29: Sequence and interspecies transfer of an aminoglycoside phosphotransferase gene (APH) of Bacillus circulans. Self-defence mechanism in antibiotic-producing organisms. Biochem J. 1986 Jan 15;233(2):383-93. doi: 10.1042/bj2330383.
• Ref 30: Daptomycin .J Antimicrob Chemother. 2018 Jan 1;73(1):1-11. doi: 10.1093/jac/dkx349. 10.1093/jac/dkx349