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Crystal structure of metallo-beta-lactamse, IMP-1, complexed with a quinolinone-based inhibitor
Structural highlights
FunctionBLAB_SERMA Confers resistance to imipenem and broad-spectrum beta-lactams. Also hydrolyzes carbapenems. Publication Abstract from PubMedMetallo-beta-lactamases (MBL) deactivate beta-lactam antibiotics through a catalytic reaction caused by two zinc ions at the active center. Since MBLs deteriorate a wide range of antibiotics, they are dangerous factors for bacterial multidrug resistance. In this work, organic synthesis, computational design, and crystal structure analysis were performed to obtain potent MBL inhibitors based on a previously identified hit compound. The hit compound comprised 3,4-dihydro-2(1H)-quinolinone linked with a phenyl-ether-methyl group via a thiazole ring. In the first step, the thiazole ring was replaced with a tertiary amine to avoid the planar structure. In the second step, we virtually modified the compound by keeping the quinolinone backbone. Every modified compound was bound to a kind of MBL, imipenemase-1 (IMP-1), and the binding pose was optimized by a molecular mechanics calculation. The binding scores were evaluated for the respective optimized binding poses. Given the predicted binding poses and calculated binding scores, candidate compounds were determined for organic syntheses. The inhibitory activities of the synthesized compounds were measured by an in vitro assay for two kinds of MBLs, IMP-1 and New Delhi metallo-beta-lactamase (NDM-1). A quinolinone connected with an amine bound with methyl-phenyl-ether-propyl and cyclohexyl-ethyl showed a 50% inhibitory concentration of 4.8 muM. An X-ray crystal analysis clarified the binding structure of a synthesized compound to IMP-1. The delta-lactam ring of quinolinone was hydrolyzed, and the generated carboxyl group was coordinated with zinc ions. The findings on the chemical structure and binding pose are expected to be a base for developing MBL inhibitors. Development of Inhibitory Compounds for Metallo-beta-lactamase through Computational Design and Crystallographic Analysis.,Kamo T, Kuroda K, Nimura S, Guo Y, Kondo S, Nukaga M, Hoshino T Biochemistry. 2024 May 21;63(10):1278-1286. doi: 10.1021/acs.biochem.4c00069. , Epub 2024 May 1. PMID:38690676[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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