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

• Type of Material: Article
• Authors: Kristin M. Papp-Wallace, Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Nhu Q. Nguyen, Case Western Reserve University; Michael R. Jacobs, Case Western Reserve University; Christopher R. Bethel, Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Melissa D. Barnes, Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Vijay Kumar, Case Western Reserve University; Saralee Bajaksouzian, Case Western Reserve University; Susan D. Rudin, Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Philip Rather, Emory University; Satish Bhaysar, Wockhardt Research Centre; Tadiparthi Ravikumar, Wockhardt Research Centre; Prasad K. Deshpande, Wockhardt Research Centre; Vijay Patil, Wockhardt Research Centre; Ravindra Yeole, Wockhardt Research Centre; Sachin S. Bhagwat, Wockhardt Research Centre; Mahesh V. Patel, Wockhardt Research Centre; Focco van den Akker, Case Western Reserve University; Robert A. Bonomo, Louis Stokes Cleveland Department of Veterans Affairs Medical Center
• Language: English
• Date: 2018-05-10
• Publisher: American Chemical Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 American Chemical Society.
• Final Published Version (URL): http://dx.doi.org/10.1021/acs.jmedchem.8b00091
• Title of Journal or Parent Work: Journal of Medicinal Chemistry
• ISSN: 0022-2623
• Volume: 61
• Issue: 9
• Start Page: 4067
• End Page: 4086
• Grant/Funding Information: This study was funded by an industry grant from Wockhardt Research Centre (WRC) to K.M.P.W., M.R.J., F.v.d.A., and R.A.B.; WRC also supplied compounds 1–3, avibactam, and relebactam powders for this work.; P.N.R. is also supported by grants from the Merit Review program and a Research Career Scientist Award, both from Department of Veterans Affairs.; The National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers R21AI114508, R01AI100560, R01AI063517, and R01AI072219 to R.A.B.; and NIAID of NIH Centers of Excellence for Translational Research (CETR) U19 AI109713 Supplemental Research Project to K.M.P.W are gratefully acknowledged.; Research reported in this publication was supported in part by funds and/or facilities provided by the Cleveland Department of Veterans Affairs; the Veterans Affairs Merit Review Program BX002872 (KMP-W); and BX001974 (RAB) from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service; and the Geriatric Research Education and Clinical Center VISN 10 to RAB.
• Keywords: BACTERIA; CRYSTAL-STRUCTURES; DISCOVERY; CARBAPENEMASE ACTIVITY; CEPHALOSPORINASE; Life Sciences & Biomedicine; OXA-24; AVIBACTAM; ACINETOBACTER-BAUMANNII; CLASS-A; Chemistry, Medicinal; Pharmacology & Pharmacy; Science & Technology; PSEUDOMONAS-AERUGINOSA
• Research Categories: Chemistry, Biochemistry; Biology, Microbiology; Health Sciences, Pharmacology

Abstract

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.