Strategic approaches to overcome resistance against Gram negative pathogens using β-lactamase inhibitors and β-lactam enhancers: The activity of three novel diazabicyclooctanes, WCK 5153, zidebactam (WCK 5107), and WCK 4234 (original) (raw)

Limited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram negative bacteria possessing broad-spectrum β-lactamases. The design of novel β-lactamase inhibitors is of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1-3) were synthesized and biochemically characterized against clinically important bacteria. Compound 3 inhibited class A, C and D β-lactamases with unprecedented k2/K values against OXA carbapenemases. Compounds 1 and 2 acylated class A and C β-lactamses rapidly, but not the tested OXAs. Compounds 1-3 formed highly stable acyl-complexes via mass spectrometry. Crystallography revealed that the KPC-2-compounds 1-3 structures adopted a "chair conformation" with the sulfate occupying the carboxylate binding region. The cefepime-2 and meropenem-3 combinations were efficiacous in murine peritonitis and neutropenic lung infection models using MDR Acinetobacte...