Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates

Jürgen Brem, Ricky Cain, Samuel Cahill, Michael A. McDonough, Ian J. Clifton, Juan-Carlos Jiménez-Castellanos, Matthew B. Avison, James Spencer, Colin W. G. Fishwick () and Christopher J. Schofield ()
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Jürgen Brem: University of Oxford
Ricky Cain: School of Chemistry, University of Leeds
Samuel Cahill: University of Oxford
Michael A. McDonough: University of Oxford
Ian J. Clifton: University of Oxford
Juan-Carlos Jiménez-Castellanos: School of Cellular and Molecular Medicine, University of Bristol
Matthew B. Avison: School of Cellular and Molecular Medicine, University of Bristol
James Spencer: School of Cellular and Molecular Medicine, University of Bristol
Colin W. G. Fishwick: School of Chemistry, University of Leeds
Christopher J. Schofield: University of Oxford

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12406

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