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Publication Abstract from PubMed

beta-Lactam antibiotics are presently the most important treatments for infections by pathogenic Escherichia coli, but their use is increasingly compromised by beta-lactamases, including the chromosomally encoded class C AmpC serine-beta-lactamases (SBLs). The diazabicyclooctane (DBO) avibactam is a potent AmpC inhibitor; the clinical success of avibactam combined with ceftazidime has stimulated efforts to optimize the DBO core. We report kinetic and structural studies, including four high-resolution crystal structures, concerning inhibition of the AmpC serine-beta-lactamase from E. coli (AmpC (EC) ) by clinically relevant DBO-based inhibitors: avibactam, relebactam, nacubactam, and zidebactam. Kinetic analyses and mass spectrometry-based assays were used to study their mechanisms of AmpC (EC) inhibition. The results reveal that, under our assay conditions, zidebactam manifests increased potency (apparent inhibition constant [K(iapp)], 0.69 muM) against AmpC (EC) compared to that of the other DBOs (K(iapp) = 5.0 to 7.4 muM) due to an approximately 10-fold accelerated carbamoylation rate. However, zidebactam also has an accelerated off-rate, and with sufficient preincubation time, all the DBOs manifest similar potencies. Crystallographic analyses indicate a greater conformational freedom of the AmpC (EC) -zidebactam carbamoyl complex compared to those for the other DBOs. The results suggest the carbamoyl complex lifetime should be a consideration in development of DBO-based SBL inhibitors for the clinically important class C SBLs.

Structural Investigations of the Inhibition of Escherichia coli AmpC beta-Lactamase by Diazabicyclooctanes.,Lang PA, Leissing TM, Page MGP, Schofield CJ, Brem J Antimicrob Agents Chemother. 2021 Jan 20;65(2):e02073-20. doi: , 10.1128/AAC.02073-20. Print 2021 Jan 20. PMID:33199391^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.