title: Cyclic Boronates Inhibit All Classes of β-Lactamases.
abstract: β-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The use of the β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, and tazobactam and, more recently, the non-β-lactam inhibitor avibactam has extended the utility of β-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-β-lactamases (MBLs), which catalyze their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors. Coproduction of MBLs and SBLs in resistant infections is thus of major clinical concern. The development of "dual-action" inhibitors, targeting both SBLs and MBLs, is of interest, but this is considered difficult to achieve due to the structural and mechanistic differences between the two enzyme classes. We recently reported evidence that cyclic boronates can inhibit both serine- and metallo-β-lactamases. Here we report that cyclic boronates are able to inhibit all four classes of β-lactamase, including the class A extended spectrum β-lactamase CTX-M-15, the class C enzyme AmpC fromPseudomonas aeruginosa, and class D OXA enzymes with carbapenem-hydrolyzing capabilities. We demonstrate that cyclic boronates can potentiate the use of β-lactams against Gram-negative clinical isolates expressing a variety of β-lactamases. Comparison of a crystal structure of a CTX-M-15:cyclic boronate complex with structures of cyclic boronates complexed with other β-lactamases reveals remarkable conservation of the small-molecule binding mode, supporting our proposal that these molecules work by mimicking the common tetrahedral anionic intermediate present in both serine- and metallo-β-lactamase catalysis.
authors.affiliation: Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom.
authors.forename: Samuel T
authors.identifier: 0000-0002-0929-4186
authors.initials: ST
authors.lastname: Cahill
authors.affiliation: School of Chemistry, University of Leeds, Leeds, United Kingdom.
authors.forename: Ricky
authors.initials: R
authors.lastname: Cain
authors.affiliation: Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom.
authors.forename: David Y
authors.initials: DY
authors.lastname: Wang
authors.affiliation: Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Lohans
authors.affiliation: Queen Mary University of London, London, United Kingdom.
authors.forename: David W
authors.initials: DW
authors.lastname: Wareham
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Henry P
authors.initials: HP
authors.lastname: Oswin
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Jabril
authors.initials: J
authors.lastname: Mohammed
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Spencer
authors.affiliation: School of Chemistry, University of Leeds, Leeds, United Kingdom.
authors.forename: Colin W G
authors.initials: CW
authors.lastname: Fishwick
authors.affiliation: Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDonough
authors.affiliation: Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom christopher.schofield@chem.ox.ac.uk jurgen.brem@chem.ox.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom christopher.schofield@chem.ox.ac.uk jurgen.brem@chem.ox.ac.uk.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brem
mesh_terms: D020816:Amino Acid Motifs; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D001897:Boronic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D003500:Cyclization; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D013816:Thermodynamics; D018440:beta-Lactam Resistance / Q000187:drug effects* / Q000235:genetics; D065093:beta-Lactamase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D001618:beta-Lactamases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001897:Boronic Acids; D011994:Recombinant Proteins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C473109:beta-lactamase CTX-M-15; C425107:beta-lactamase OXA-10; C048795:AmpC beta-lactamases; D001618:beta-Lactamases
keywords: antibiotic resistance; beta-lactamases; beta-lactams; boronate; carbapenemase; inhibitors; metalloenzymes