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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Christopher J. Schofield, 2016. "Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates," Nature Communications, Nature, vol. 7(1), pages 1-8, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12406
    DOI: 10.1038/ncomms12406
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