Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates

Samuel T. Cahill, Jonathan M. Tyrrell, Iva Hopkins Navratilova, Karina Calvopiña, Sean W. Robinson, Christopher T Lohans, Michael A. McDonough, Ricky Cain, Colin W. G. Fishwick, Matthew B. Avison, Timothy R. Walsh, Christopher J. Schofield (Lead / Corresponding author), Jürgen Brem

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)
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Abstract

Background: The β-lactam antibiotics represent the most successful drug class for treatment of bacterial infections. Resistance to them, importantly via production of β-lactamases, which collectively are able to hydrolyse all classes of β-lactams, threatens their continued widespread use. Bicyclic boronates show potential as broad spectrum inhibitors of the mechanistically distinct serine- (SBL) and metallo- (MBL) β-lactamase families.

Methods: Using biophysical methods, including crystallographic analysis, we have investigated the binding mode of bicyclic boronates to clinically important β-lactamases. Induction experiments and agar-based MIC screening against MDR-Enterobacteriaceae (n = 132) were used to evaluate induction properties and the in vitro efficacy of a bicyclic boronate in combination with meropenem.

Results: Crystallographic analysis of a bicyclic boronate in complex with AmpC from Pseudomonas aeruginosa reveals it binds to form a tetrahedral boronate species. Microbiological studies on the clinical coverage (in combination with meropenem) and induction of β-lactamases by bicyclic boronates further support the promise of such compounds as broad spectrum β-lactamase inhibitors.

Conclusions: Together with reported studies on the structural basis of their inhibition of class A, B and D β-lactamases, biophysical studies, including crystallographic analysis, support the proposal that bicyclic boronates mimic tetrahedral intermediates common to SBL and MBL catalysis.

General Significance: Bicyclic boronates are a new generation of broad spectrum inhibitors of both SBLs and MBLs.

Original languageEnglish
Pages (from-to)742-748
Number of pages7
JournalBiochimica et Biophysica Acta: General Subjects
Volume1863
Issue number4
Early online date7 Feb 2019
DOIs
Publication statusPublished - 1 Apr 2019

Keywords

  • Antimicrobial clinical coverage
  • Cyclic boronate inhibitors
  • Metallo and serine β-lactamase inhibition
  • Transition state analogue
  • β-lactam antibiotic resistance
  • β-lactamase induction

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