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, Jim Spencer, Colin W G Fishwick, Christopher J Schofield

Research output: Contribution to journalArticle (Academic Journal)

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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.

Original languageEnglish
Article number12406
Number of pages8
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 8 Aug 2016

Keywords

  • Enzymes
  • Structural biology

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    Brem, J., Cain, R., Cahill, S., McDonough, M. A., Clifton, I. J., Jiménez-Castellanos, J-C., Avison, M. B., Spencer, J., Fishwick, C. W. G., & Schofield, C. J. (2016). Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates. Nature Communications, 7, [12406]. https://doi.org/10.1038/ncomms12406