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Publication Abstract from PubMed

beta-lactamases inactivate beta-lactam antibiotics leading to drug resistance. Consequently, inhibitors of beta-lactamases can combat this resistance, and the beta-lactamase inhibitory protein (BLIP) is a naturally occurring inhibitor. The widespread CTX-M-14 and CTX-M-15 beta-lactamases have an 83% sequence identity. In this study, we show that BLIP weakly inhibits CTX-M-14 but potently inhibits CTX-M-15. The structure of the BLIP/CTX-M-15 complex reveals that binding is associated with a conformational change of an active site loop of beta-lactamase. Surprisingly, the loop structure in the complex is similar to that in a drug-resistant variant (N106S) of CTX-M-14. We hypothesized that the pre-established favorable loop conformation of the N106S mutant would facilitate binding. The N106S substitution results in a ~100- and 10-fold increase in BLIP inhibition potency for CTX-M-14 and CTX-M-15, respectively. Thus, this indicates that an active site loop in beta-lactamase toggles between conformations that control antibiotic hydrolysis and inhibitor susceptibility. These findings highlight the role of accessible active site conformations in controlling enzyme activity and inhibitor susceptibility as well as the influence of mutations in selectively stabilizing discrete conformations.

An active site loop toggles between conformations to control antibiotic hydrolysis and inhibition potency for CTX-M beta-lactamase drug-resistance enzymes.,Lu S, Hu L, Lin H, Judge A, Rivera P, Palaniappan M, Sankaran B, Wang J, Prasad BVV, Palzkill T Nat Commun. 2022 Nov 7;13(1):6726. doi: 10.1038/s41467-022-34564-3. PMID:36344533^[1]

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