Drug Information

Drug (ID: DG00048) and It's Reported Resistant Information

• Name: Doripenem
• Synonyms: Doribax; S 4661; S-4661; Doripenem (USAN/INN); (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S,5S)-5-[(sulfamoylamino)methyl]pyrrolidin-3-yl]sulfanyl-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
• Indication:
  In total 2 Indication(s)
  Urinary tract infection [ICD-11: GC08]; Approved; [1]
  Gram-positive bacterial infection [ICD-11: 1B74-1F40]; Phase 3; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Malaria [ICD-11: 1F45]; [1]
  Melioidosis [ICD-11: 1C42]; [2], [3]
• Target: Bacterial Dihydropteroate synthetase (Bact folP); DHPS_ECOLI; [1]
• Formula: C15H24N4O6S2
• IsoSMILES: C[C@@H]1[C@@H]2[C@H](C(=O)N2C(=C1S[C@H]3C[C@H](NC3)CNS(=O)(=O)N)C(=O)O)[C@@H](C)O
• InChI: 1S/C15H24N4O6S2/c1-6-11-10(7(2)20)14(21)19(11)12(15(22)23)13(6)26-9-3-8(17-5-9)4-18-27(16,24)25/h6-11,17-18,20H,3-5H2,1-2H3,(H,22,23)(H2,16,24,25)/t6-,7-,8+,9+,10-,11-/m1/s1
• InChIKey: AVAACINZEOAHHE-VFZPANTDSA-N
• PubChem CID: 73303
• ChEBI ID: CHEBI:135928
• TTD Drug ID: D03QWT
• INTEDE ID: DR0534
• DrugBank ID: DB06211

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Melioidosis [ICD-11: 1C42]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Outer membrane porin (OMP38) [2], [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Melioidosis [ICD-11: 1C42.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Burkholderia pseudomallei isolates; 28450
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Bps is highly resistant to many antimicrobial agents and this resistance may result from the low drug permeability of outer membrane proteins, known as porins.An Escherichia coli strain defective in most porins, but expressing BpsOmp38, exhibited considerably lower antimicrobial susceptibility than the control strain. In addition, mutation of Tyr119, the most prominent pore-lining residue in BpsOmp38, markedly altered membrane permeability, substitution with Ala (mutant BpsOmp38Y119A) enhanced uptake of the antimicrobial agents, while substitution with Phe (mutant BpsOmp38Y119F) inhibited uptake.

Key Molecule: Outer membrane porin (OMP38) [2], [3]

• Molecule Alteration: Missense mutation; p.Y119F
• Resistant Disease: Melioidosis [ICD-11: 1C42.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Burkholderia pseudomallei isolates; 28450
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Bps is highly resistant to many antimicrobial agents and this resistance may result from the low drug permeability of outer membrane proteins, known as porins.An Escherichia coli strain defective in most porins, but expressing BpsOmp38, exhibited considerably lower antimicrobial susceptibility than the control strain. In addition, mutation of Tyr119, the most prominent pore-lining residue in BpsOmp38, markedly altered membrane permeability, substitution with Ala (mutant BpsOmp38Y119A) enhanced uptake of the antimicrobial agents, while substitution with Phe (mutant BpsOmp38Y119F) inhibited uptake.

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.

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: Functional reconstitution, gene isolation and topology modelling of porins from Burkholderia pseudomallei and Burkholderia thailandensis. Biochem J. 2004 Feb 1;377(Pt 3):579-87. doi: 10.1042/BJ20031118.
• Ref 3: Porin involvement in cephalosporin and carbapenem resistance of Burkholderia pseudomallei. PLoS One. 2014 May 1;9(5):e95918. doi: 10.1371/journal.pone.0095918. eCollection 2014.