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Author Notes:

Krisztina Papp -Wallace:Phone: 216-791-3800 ×6230. Krisztina.Papp@va.gov..

Focco van den Akker: Phone: 216-368-8511. fxv5@case.edu

Robert Bonomo:Phone:216-791-3800 × 4801. Robert.Bonomo@va.gov

K.M.P.W, M.R.J, S.S.B, M.V.P, F.v.d.A., and R.A.B. designed the project.

K.M.P.W., N.Q.N, C.R.B., M.D.B, V.K., S.B., S.D.R., S.B., T.R., P.K.D., V.P., and R.Y. performed experiments.

P.N.R provided critical reagents.

K.M.P.W, M.R.J, S.S.B, M.V.P, F.v.d.A., and R.A.B. analyzed the results together and wrote the manuscript.

All authors read and approved the manuscript.

We thank the beamline personnel at SSRL for help with data collection.

In addition, we thank David Lodowski and APS for help with collecting the OXA-24 data set.

The authors declare the following competing financial interest(s): S.B., T.R., P.K.D., V.P., R.Y., S.S.B., and M.V.P. are employees of Wockhardt Research Centre, Aurangabad, India.

Subjects:

Research Funding:

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.

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.

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.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Chemistry, Medicinal
  • Pharmacology & Pharmacy
  • ACINETOBACTER-BAUMANNII
  • PSEUDOMONAS-AERUGINOSA
  • CLASS-A
  • CARBAPENEMASE ACTIVITY
  • CRYSTAL-STRUCTURES
  • AVIBACTAM
  • OXA-24
  • CEPHALOSPORINASE
  • DISCOVERY
  • BACTERIA

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

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Journal Title:

Journal of Medicinal Chemistry

Volume:

Volume 61, Number 9

Publisher:

, Pages 4067-4086

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2018 American Chemical Society.

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