Boronic Acid Transition State Inhibitors as Potent Inactivators of KPC and CTX-M β-Lactamases: Biochemical and Structural Analyses

作者：T. A. Alsenani, M.M. Rodríguez, Bárbara Ghiglione, Magdalena A. Taracila, María F. Mojica, Laura J. Rojas, Andrea M. Hujer, Gabriel Gutkind, Christopher R. Bethel, Philip N. Rather, Maria Luisa Introvigne, Fabio Prati, Emilia Caselli, P.P. Power, Focco van den Akker, Robert A. Bonomo · 发表于：Antimicrobial Agents and Chemotherapy · 年份：2023 · DOI：10.1128/aac.00930-22 · 被引用次数：11 · 研究领域：Antibiotic Resistance in Bacteria、Tuberculosis Research and Epidemiology、Pneumonia and Respiratory Infections

models of CTX-M-96 with these two BATSIs show that interaction in the CTX-M-96-S02030 and CTX-M-96-MB_076 complexes were overall equivalent to that observed for the crystallographic structure of KPC-2-S02030 and KPC-2-MB_076. The tetrahedral interaction surrounding the boron atom from S02030 and MB_076 creates a favorable hydrogen bonding network with S70, S130, N132, N170, and S237. However, the changes from W105 in KPC-2 to Y105 in CTX-M-96 and the missing residue R220 in CTX-M-96 alter the arrangement of the inhibitors in the active site of CTX-M-96, partially explaining the difference in kinetic parameters. The novel BATSI scaffolds studied here advance our understanding of structure-activity relationships (SARs) and illustrate the importance of new approaches to β-lactamase inhibitor design.