title: Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates.
abstract: β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as 'transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent β-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-β-lactamases, and which could also have antimicrobial activity through inhibition of PBPs.
authors: Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors: Jürgen
authors: J
authors: Brem
authors: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors: Ricky
authors: R
authors: Cain
authors: Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors: Samuel
authors: 0000-0002-0929-4186
authors: S
authors: Cahill
authors: Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors: Michael A
authors: MA
authors: McDonough
authors: Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors: Ian J
authors: IJ
authors: Clifton
authors: School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, UK.
authors: Juan-Carlos
authors: JC
authors: Jiménez-Castellanos
authors: School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, UK.
authors: Matthew B
authors: MB
authors: Avison
authors: School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, UK.
authors: James
authors: J
authors: Spencer
authors: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors: Colin W G
authors: CW
authors: Fishwick
authors: Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors: Christopher J
authors: CJ
authors: Schofield
mesh_terms: D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology*; D003500:Cyclization; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001897:Boronic Acids; D004791:Enzyme Inhibitors; D046915:Penicillin-Binding Proteins; D012694:Serine; D001618:beta-Lactamases