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.