title: Interactions of OP0595, a Novel Triple-Action Diazabicyclooctane, with β-Lactams against OP0595-Resistant Enterobacteriaceae Mutants.
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.
authors.affiliation: Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, United Kingdom Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom d.livermore@uea.ac.uk.
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
authors.affiliation: Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, United Kingdom.
authors.forename: Marina
authors.initials: M
authors.lastname: Warner
authors.affiliation: Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, United Kingdom.
authors.forename: Shazad
authors.initials: S
authors.lastname: Mushtaq
authors.affiliation: Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Woodford
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001398:Aztreonam / Q000494:pharmacology*; D000077723:Cefepime; D002511:Cephalosporins / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D007769:Lactams / Q000494:pharmacology*; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009154:Mutation; D046915:Penicillin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D010878:Piperacillin / Q000494:pharmacology*; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013845:Thienamycins / Q000494:pharmacology; D018440:beta-Lactam Resistance / Q000235:genetics; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D002511:Cephalosporins; D004338:Drug Combinations; D029968:Escherichia coli Proteins; D007769:Lactams; D046915:Penicillin-Binding Proteins; D020033:Protein Isoforms; D013845:Thienamycins; D000077723:Cefepime; C000608518:nacubactam; C582982:MrdA protein, E coli; D001618:beta-Lactamases; D000077731:Meropenem; D001398:Aztreonam; D010878:Piperacillin