Structural Basis of Metallo-β-Lactamase Inhibition by Captopril Stereoisomers
β-Lactams are the most successful antibacterials, but their effectiveness is threatened by resistance, most importantly by production of serine- and metallo-β-lactamases (MBLs). MBLs are of increasing concern because they catalyze the hydrolysis of almost all β-lactam antibiotics, including recent-g...
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Published in | Antimicrobial agents and chemotherapy Vol. 60; no. 1; pp. 142 - 150 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Microbiology
01.01.2016
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Subjects | |
Online Access | Get full text |
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Summary: | β-Lactams are the most successful antibacterials, but their effectiveness is threatened by resistance, most importantly by production of serine- and metallo-β-lactamases (MBLs). MBLs are of increasing concern because they catalyze the hydrolysis of almost all β-lactam antibiotics, including recent-generation carbapenems. Clinically useful serine-β-lactamase inhibitors have been developed, but such inhibitors are not available for MBLs. l-Captopril, which is used to treat hypertension via angiotensin-converting enzyme inhibition, has been reported to inhibit MBLs by chelating the active site zinc ions via its thiol(ate). We report systematic studies on B1 MBL inhibition by all four captopril stereoisomers. High-resolution crystal structures of three MBLs (IMP-1, BcII, and VIM-2) in complex with either the l- or d-captopril stereoisomer reveal correlations between the binding mode and inhibition potency. The results will be useful in the design of MBL inhibitors with the breadth of selectivity required for clinical application against carbapenem-resistant Enterobacteriaceae and other organisms causing MBL-mediated resistant infections. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Citation Brem J, van Berkel SS, Zollman D, Lee SY, Gileadi O, McHugh PJ, Walsh TR, McDonough MA, Schofield CJ. 2016. Structural basis of metallo-β-lactamase inhibition by captopril stereoisomers. Antimicrob Agents Chemother 60:142–150. doi:10.1128/AAC.01335-15. J.B., S.S.V.B., and D.Z. are co-first authors. |
ISSN: | 0066-4804 1098-6596 |
DOI: | 10.1128/AAC.01335-15 |