Interactions of OP0595, a Novel Triple-Action Diazabicyclooctane, with β-Lactams against OP0595-Resistant Enterobacteriaceae Mutants

Antimicrob Agents Chemother. 2015 Nov 9;60(1):554-60. doi: 10.1128/AAC.02184-15. Print 2016 Jan.

Abstract

OP0595 is a novel diazabicyclooctane which, like avibactam, inhibits class A and C β-lactamases. In addition, unlike avibactam, it has antibacterial activity, with MICs of 0.5 to 4 μg/ml for most members of the family Enterobacteriaceae, owing to inhibition of PBP2; moreover, it acts synergistically with PBP3-active β-lactams independently of β-lactamase inhibition, via an "enhancer effect." Enterobacteriaceae mutants stably resistant to 16 μg/ml OP0595 were selected on agar at frequencies of approximately 10(-7). Unsurprisingly, OP0595 continued to potentiate substrate β-lactams against mutants derived from Enterobacteriaceae with OP0595-inhibited class A and C β-lactamases. Weaker potentiation of partners, especially aztreonam, cefepime, and piperacillin--less so meropenem--remained frequent for OP0595-resistant Enterobacteriaceae mutants lacking β-lactamases or with OP0595-resistant metallo-β-lactamases (MBLs), indicating that the enhancer effect is substantially retained even when antibiotic activity is lost.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Azabicyclo Compounds / pharmacology*
  • Aztreonam / pharmacology*
  • Cefepime
  • Cephalosporins / pharmacology*
  • Drug Combinations
  • Drug Synergism
  • Enterobacteriaceae / drug effects*
  • Enterobacteriaceae / genetics
  • Enterobacteriaceae / metabolism
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism
  • Gene Expression
  • Lactams / pharmacology*
  • Meropenem
  • Microbial Sensitivity Tests
  • Mutation
  • Penicillin-Binding Proteins / genetics
  • Penicillin-Binding Proteins / metabolism
  • Piperacillin / pharmacology*
  • Plasmids / chemistry
  • Plasmids / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Thienamycins / pharmacology
  • beta-Lactam Resistance / genetics
  • beta-Lactamases / genetics
  • beta-Lactamases / metabolism

Substances

  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Cephalosporins
  • Drug Combinations
  • Escherichia coli Proteins
  • Lactams
  • OP0595
  • Penicillin-Binding Proteins
  • Protein Isoforms
  • Thienamycins
  • Cefepime
  • MrdA protein, E coli
  • beta-Lactamases
  • Meropenem
  • Aztreonam
  • Piperacillin