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 <b>1</b>–<b>3</b>, respectively), were synthesized and biochemically characterized against clinically important bacteria. Compound <b>3</b> inhibited class A, C, and D β-lactamases with unprecedented <i>k</i>₂/<i>K</i> values against OXA carbapenemases. Compounds <b>1</b> and <b>2</b> acylated class A and C β-lactamses rapidly but not the tested OXAs. Compounds <b>1</b>–<b>3</b> formed highly stable acyl-complexes as demonstrated by mass spectrometry. Crystallography revealed that <b>1</b>–<b>3</b> complexed with KPC-2 adopted a “chair conformation” with the sulfate occupying the carboxylate binding region. The cefepime-<b>2</b> and meropenem-<b>3</b> combinations were effective in murine peritonitis and neutropenic lung infection models caused by MDR <i>Acinetobacter baumannii</i>. Compounds <b>1</b>–<b>3</b> are novel β-lactamase inhibitors that demonstate potent cross-class inhibition, and clinical studies targeting MDR infections are warranted