Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 9, Pages 4067-4086Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00091
Keywords
-
Categories
Funding
- Wockhardt Research Centre (WRC)
- Cleveland Department of Veterans Affairs
- Veterans Affairs Merit Review Program from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service [BX002872, BX001974]
- Geriatric Research Education and Clinical Center [VISN 10]
- Merit Review program from Department of Veterans Affairs
- Research Career Scientist Award from Department of Veterans Affairs
- National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [R21A1114508, R01A1100560, R01A1063517, R01A1072219]
- NIAID of NIH Centers of Excellence for Translational Research (CETR) [U19 AI109713]
Ask authors/readers for more resources
Limited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram-negative bacteria possessing broad-spectrum beta-lactamases. The design of novel beta-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 beta-lactamases with unprecedented k2/K values against OXA carbapenemases. Compounds 1 and 2 acylated class A and C beta-lactamses rapidly but not the tested OXAs. Compounds 1-3 formed highly stable aryl-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 fi-lactamase inhibitors that demonstate potent cross-class inhibition, and clinical studies targeting MDR infections are warranted.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available