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Experimental Therapeutics

Cyclic Boronates Inhibit All Classes of β-Lactamases

Samuel T. Cahill, Ricky Cain, David Y. Wang, Christopher T. Lohans, David W. Wareham, Henry P. Oswin, Jabril Mohammed, James Spencer, Colin W. G. Fishwick, Michael A. McDonough, Christopher J. Schofield, Jürgen Brem
Samuel T. Cahill
aChemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
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Ricky Cain
dSchool of Chemistry, University of Leeds, Leeds, United Kingdom
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David Y. Wang
aChemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
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Christopher T. Lohans
aChemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
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David W. Wareham
bQueen Mary University of London, London, United Kingdom
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Henry P. Oswin
cSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
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Jabril Mohammed
cSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
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James Spencer
cSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
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Colin W. G. Fishwick
dSchool of Chemistry, University of Leeds, Leeds, United Kingdom
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Michael A. McDonough
aChemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
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Christopher J. Schofield
aChemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
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Jürgen Brem
aChemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
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DOI: 10.1128/AAC.02260-16
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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 from Pseudomonas 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.

FOOTNOTES

    • Received 21 October 2016.
    • Returned for modification 20 December 2016.
    • Accepted 17 January 2017.
    • Accepted manuscript posted online 23 January 2017.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.02260-16 .

  • Copyright © 2017 Cahill et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license .

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Cyclic Boronates Inhibit All Classes of β-Lactamases
Samuel T. Cahill, Ricky Cain, David Y. Wang, Christopher T. Lohans, David W. Wareham, Henry P. Oswin, Jabril Mohammed, James Spencer, Colin W. G. Fishwick, Michael A. McDonough, Christopher J. Schofield, Jürgen Brem
Antimicrobial Agents and Chemotherapy Mar 2017, 61 (4) e02260-16; DOI: 10.1128/AAC.02260-16

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Cyclic Boronates Inhibit All Classes of β-Lactamases
Samuel T. Cahill, Ricky Cain, David Y. Wang, Christopher T. Lohans, David W. Wareham, Henry P. Oswin, Jabril Mohammed, James Spencer, Colin W. G. Fishwick, Michael A. McDonough, Christopher J. Schofield, Jürgen Brem
Antimicrobial Agents and Chemotherapy Mar 2017, 61 (4) e02260-16; DOI: 10.1128/AAC.02260-16
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KEYWORDS

Anti-Bacterial Agents
Boronic Acids
Enterobacteriaceae
beta-lactam resistance
beta-lactamase inhibitors
beta-lactamases
antibiotic resistance
beta-lactamases
beta-lactams
boronate
carbapenemase
inhibitors
metalloenzymes

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