Strategic Approaches to Overcome Resistance against Gram-Negative Pathogens Using β‑Lactamase Inhibitors and β‑Lactam Enhancers: Activity of Three Novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234

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, respectively), 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 as demonstrated by mass spectrometry. Crystallography
revealed that 1–3 complexed with KPC-2 adopted a “chair conformation” with the
sulfate occupying the carboxylate binding region. The cefepime-2 and meropenem-3 combinations were effective
in murine peritonitis and neutropenic lung infection models caused by
MDR Acinetobacter baumannii. Compounds 1–3 are novel β-lactamase inhibitors that
demonstate potent cross-class inhibition, and clinical studies targeting
MDR infections are warranted.