Drug Information

Drug (ID: DG00227) and It's Reported Resistant Information

• Name: Meropenem
• Synonyms: MEPM; MERONEM; Meropen; Merrem; Meropenem anhydrous; Mepem (TN); Meronem (TN); Meropen (TN); Meropenem (INN); Merrem (TN); Neopenem (TN); SM-7338; Meronem; Merrem I.V. (TN); (1R,5S,6S)-2-[(3S,5S)-5-(dimethylaminocarbonyl)pyrrolidin-3-ylthio]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid trihydrate; (2S,3R,4R)-2-[(1S,2R)-1-carboxy-2-hydroxypropyl]-4-{[(3S,5R)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl}-3-methyl-3,4-dihydro-2H-pyrrole-5-carboxylic acid; (4R,5S,6S)-3-[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; (4R,5S,6S)-3-{[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]thio}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; (5S,6S)-3-((3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-ylthio)-6-((S)-1-hydroxyethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid; (6S)-2-{[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-1beta-methyl-2,3-didehydro-1-carbapenam-3-carboxylic acid
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (7 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [2]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [2]
  Malaria [ICD-11: 1F45]; [1]
  Non-tuberculous mycobacteria infection [ICD-11: 1B21]; [3]
  Pneumonia [ICD-11: CA40]; [4]
  Pyothorax [ICD-11: CA44]; [4]
  Sclerosing cholangitis [ICD-11: DB96]; [5]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Cholera [ICD-11: 1A00]; [6]
• Target: Bacterial Penicillin binding protein (Bact PBP); NOUNIPROTAC; [1]
• Formula: C17H25N3O5S
• IsoSMILES: C[C@@H]1[C@@H]2[C@H](C(=O)N2C(=C1S[C@H]3C[C@H](NC3)C(=O)N(C)C)C(=O)O)[C@@H](C)O
• InChI: 1S/C17H25N3O5S/c1-7-12-11(8(2)21)16(23)20(12)13(17(24)25)14(7)26-9-5-10(18-6-9)15(22)19(3)4/h7-12,18,21H,5-6H2,1-4H3,(H,24,25)/t7-,8-,9+,10+,11-,12-/m1/s1
• InChIKey: DMJNNHOOLUXYBV-PQTSNVLCSA-N
• PubChem CID: 441130
• ChEBI ID: CHEBI:43968
• TTD Drug ID: D0O5FY
• VARIDT ID: DR01200
• INTEDE ID: DR2491
• DrugBank ID: DB00760

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: Beta-lactamase-like protein (VARG) [6]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Vibrio cholerae CVD101; 1854
• Mechanism Description: A gel-shift analysis was used to determine if VarR bound to the promoter regions of the resistance genes. Consistent with the regulation of these resistance genes, VarR binds to three distinct intergenic regions, varRG, varGA and varBC located upstream and adjacent to varG, varA and varC, respectively. VarR can act as a repressor at the varRG promoter region; whilst this repression was relieved upon addition of Beta-lactams, these did not dissociate the VarR/varRG-DNA complex, indicating that the de-repression of varR by Beta-lactams is indirect.

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: CATB10-Ib variant (CATB10) [7]

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

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

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

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: TolC family outer membrane protein (TOLC) [8]

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

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Pyruvate decarboxylase 5 (PDC5) [9], [10]

• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• 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) [9], [10]

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

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• 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.

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) [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cutaneous bacterial infection [ICD-11: 1B21.4]
• 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.

Malaria [ICD-11: 1F45]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: CAM-1 carbapenemase (CAM1) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pseudomonas infection [ICD-11: 1F45.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa N17-01167; 287
• In Vitro Model: Pseudomonas aeruginosa N17-01173; 287
• In Vitro Model: Pseudomonas aeruginosa N17-02436; 287
• In Vitro Model: Pseudomonas aeruginosa N17-02437; 287
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: Vitek 2 assay; Etest assay
• Mechanism Description: A novel class B Beta-lactamase gene, blaCAM-1, exhibited resistance to imipenem, meropenem, doripenem, cefotaxime, ceftazidime, cefoxitin, piperacillin/tazobactam, ceftazidime/avibactam and ceftolozane/tazobactam.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: OmpK37 (OMPK37) [11]

• Molecule Alteration: Expression; Inherence
• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Klebsiella pneumoniae strain CSUB10R; 573
• In Vitro Model: Klebsiella pneumoniae strain CSUB10S; 573
• In Vitro Model: Klebsiella pneumoniae strain LB4; 573
• In Vitro Model: Klebsiella pneumoniae strain LB66; 573
• In Vitro Model: Klebsiella pneumoniae strain SD8; 573
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: Due to its porin deficiency, strain CSUB10R is more resistant to Beta-lactams than is parental strain CSUB10S. As expected, for k. pneumoniae CSUB10R expressing Ompk36 or Ompk35, the MICs reverted to values similar to those observed for strain CSUB10S.

References

• Ref 1: Identification of a novel metallo-Beta-lactamase, CAM-1, in clinical Pseudomonas aeruginosa isolates from Canada. J Antimicrob Chemother. 2019 Jun 1;74(6):1563-1567. doi: 10.1093/jac/dkz066.
• Ref 2: 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 3: Daptomycin .J Antimicrob Chemother. 2018 Jan 1;73(1):1-11. doi: 10.1093/jac/dkx349. 10.1093/jac/dkx349
• Ref 4: Community-acquired Pseudomonas aeruginosa pneumonia manifested by bloody pleural effusion in a previously healthy infant: A case reportJ Clin Lab Anal. 2022 Jun;36(6):e24466. doi: 10.1002/jcla.24466. Epub 2022 May 13.
• Ref 5: Treatment options for other hepatic malignancies .Liver Transpl. 2000 Nov;6(6 Suppl 2):S23-9. doi: 10.1053/jlts.2000.18687. 10.1053/jlts.2000.18687
• Ref 6: The Vibrio cholerae var regulon encodes a metallo-Beta-lactamase and an antibiotic efflux pump, which are regulated by VarR, a LysR-type transcription factor. PLoS One. 2017 Sep 12;12(9):e0184255. doi: 10.1371/journal.pone.0184255. eCollection 2017.
• Ref 7: 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 8: 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 9: 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 10: 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 11: Identification and characterization of a new porin gene of Klebsiella pneumoniae: its role in beta-lactam antibiotic resistance. J Bacteriol. 1999 May;181(9):2726-32. doi: 10.1128/JB.181.9.2726-2732.1999.