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Publication - Professor Matthew Avison

    Studies on the Inhibition of AmpC and other β-Lactamases by Cyclic Boronates

    Citation

    Cahill, ST, Tyrrell, JM, Navratilova, IH, Calvopiña, K, Robinson, SW, Lohans, CT, McDonough, MA, Cain, R, Fishwick, CW, Avison, MB, Walsh, TR, Schofield, CJ & Brem, J, 2019, ‘Studies on the Inhibition of AmpC and other β-Lactamases by Cyclic Boronates’. Biochimica et Biophysica Acta (BBA) - General Subjects, vol 1863., pp. 742-748

    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.

    Full details in the University publications repository