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X-ray structure of the NDM-4 beta-lactamase from Klebsiella pneumonia with L-Captopril boundX-ray structure of the NDM-4 beta-lactamase from Klebsiella pneumonia with L-Captopril bound
Structural highlights
FunctionBLAN1_KLEPN Confers resistance to many beta-lactam antibiotics, including some carbapenems. Does not confer resistance to the polymixin colistin or the fluoroquinolone ciprofloxacin. Publication Abstract from PubMedThe bacterial metallo-beta-lactamases (MBLs) catalyze the inactivation of beta-lactam antibiotics. Identifying novel pharmacophores remains crucial for the clinical development of additional MBL inhibitors. Previously, 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid, hereafter referred to as 1,2-HPT-6-COOH, was reported as a low cytotoxic nanomolar beta-lactamase inhibitor of Verona-integron-encoded metallo-beta-lactamase 2 (VIM-2), capable of rescuing beta-lactam antibiotic activity. In this study, we explore its exact mechanism of inhibition and the extent of its activity through structural characterization of its binding to New Delhi metallo-beta-lactamase 4 (NDM-4) and its inhibitory activity against both NDM-1 and NDM-4. Of all the structure-validated MBL inhibitors available, 1,2-HPT-6-COOH is the first discovered compound capable of forming an octahedral coordination sphere with Zn2 of the binuclear metal center. This unexpected mechanism of action provides important insight for the further optimization of 1,2-HPT-6-COOH and the identification of additional pharmacophores for MBL inhibition. Characterization of a novel inhibitor for the New Delhi metallo-beta-lactamase-4: implications for drug design and combating bacterial drug resistance.,Thoden JB, Benin BM, Priebe A, Shin WS, Muthyala R, Sham YY, Holden HM J Biol Chem. 2023 Aug 5:105135. doi: 10.1016/j.jbc.2023.105135. PMID:37549809[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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