by
Kristin M. Papp-Wallace;
Nhu Q. Nguyen;
Michael R. Jacobs;
Christopher R. Bethel;
Melissa D. Barnes;
Vijay Kumar;
Saralee Bajaksouzian;
Susan D. Rudin;
Philip Rather;
Satish Bhaysar;
Tadiparthi Ravikumar;
Prasad K. Deshpande;
Vijay Patil;
Ravindra Yeole;
Sachin S. Bhagwat;
Mahesh V. Patel;
Focco van den Akker;
Robert A. Bonomo
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 k 2 /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.