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-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.
Department of Chemistry, University of Oxford, Oxford, United Kingdom.
Jürgen
J
Brem
Department of Chemistry, University of Oxford, Oxford, United Kingdom.
Sander S
SS
van Berkel
Department of Chemistry, University of Oxford, Oxford, United Kingdom.
David
D
Zollman
Department of Chemistry, University of Oxford, Oxford, United Kingdom.
Sook Y
SY
Lee
Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.
Opher
O
Gileadi
Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Peter J
PJ
McHugh
Department of Microbiology and Infectious Diseases, Institute of Infection and Immunity, Heath Hospital, Cardiff, United Kingdom.
Timothy R
TR
Walsh
Department of Chemistry, University of Oxford, Oxford, United Kingdom michael.mcdonough@chem.ox.ac.uk christopher.schofield@chem.ox.ac.uk.
Michael A
MA
McDonough
Department of Chemistry, University of Oxford, Oxford, United Kingdom michael.mcdonough@chem.ox.ac.uk christopher.schofield@chem.ox.ac.uk.
Christopher J
CJ
Schofield
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002216:Captopril / Q000737:chemistry / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D058492:Drug Repositioning; D004755:Enterobacteriaceae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D015870:Gene Expression; D006868:Hydrolysis; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018440:beta-Lactam Resistance / Q000187:drug effects / Q000235:genetics; D065093:beta-Lactamase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D001618:beta-Lactamases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D000900:Anti-Bacterial Agents; D015780:Carbapenems; D011994:Recombinant Proteins; D065093:beta-Lactamase Inhibitors; D002216:Captopril; C455979:beta-lactamase BcII; C409201:beta-lactamase IMP-1; C425108:beta-lactamase bla(vim-2); D001618:beta-Lactamases