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

(2019) Biochim Biophys Acta Gen Subj 1863: 742-748

• PubMed: 30738906 Search on PubMed
• DOI: https://doi.org/10.1016/j.bbagen.2019.02.004
• Primary Citation of Related Structures:  
  6I30


• PubMed Abstract: 
  

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

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Organizational Affiliation: 

Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.