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Structural basis of metallo-β-lactamase inhibition by captopril stereoisomers

DOI: 10.1128/AAC.01335-15 DOI Help
PMID: 26482303 PMID Help

Authors: Jurgen Brem (University of Oxford) , Sander S. Van Berkel (University of Oxford) , David Zollman (University of Oxford) , Sook Y. Lee (University of Oxford) , Opher Gileadi (University of Oxford) , Peter J. Mchugh (University of Oxford) , Timothy R. Walsh (Heath Hospital, Cardiff) , Michael Mcdonough (Department of Chemistry, University of Oxford) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Antimicrobial Agents And Chemotherapy

State: Published (Approved)
Published: October 2015

Abstract: 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 catalyse 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, used to treat hypertension via angiotensin-converting enzyme inhibition, has been reported to inhibit MBLs by chelating to 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 L-or D-captopril stereoisomers reveal correlations between the binding modes 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 MBL mediated resistant infections.

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography