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

DOI: 10.1016/j.bbagen.2019.02.004 DOI Help

Authors: Samuel T. Cahill (University of Oxford) , Jonathan M. Tyrrell (Cardiff University) , Iva Hopkins Navratilova (University of Dundee; Research Complex at Harwell) , Karina Calvopina (University of Bristol) , Sean W. Robinson (Kinetic Discovery Ltd) , Christopher T. Lohans (University of Oxford) , Michael A. Mcdonough (University of Oxford) , Ricky Cain (University of Leeds) , Colin W. G. Fishwick (University of Leeds) , Matthew B. Avison (University of Bristol) , Timothy R. Walsh (Cardiff University) , Christopher J. Schofield (University of Oxford) , Jurgen Brem (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochimica Et Biophysica Acta (bba) - General Subjects , VOL 1863 , PAGES 742 - 748

State: Published (Approved)
Published: April 2019

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.

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

Subject Areas: Biology and Bio-materials, Medicine

Beamlines: I04-Macromolecular Crystallography