Interactions of OP0595, a novel triple-action diazabicyclooctane, with β-lactams against OP0595-resistant Enterobacteriaceae mutants

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 0.5-4 μg/ml for most Enterobacteriaceae, owing to inhibition of PBP2; moreover it synergizes 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 approx. 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, indicating that the enhancer effect is substantially retained even when antibiotic activity is lost.