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Structural/mechanistic insights into the efficacy of non-classical β-lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates

DOI: 10.1111/mmi.13831 DOI Help

Authors: Karina Calvopina (University of Bristol) , Philip Hinchliffe (University of Bristol) , Jurgen Brem (University of Oxford) , Kate J. Heesom (Bristol University Proteomics Facility) , Samar Johnson (University of Bristol) , Ricky Cain (University of Leeds) , Christopher T. Lohans (University of Oxford) , Colin W. G. Fishwick (University of Leeds) , Christopher J. Schofield (University of Oxford) , James Spencer (University of Bristol) , Matthew B. Avison (University of Bristol)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Microbiology

State: Published (Approved)
Published: September 2017
Diamond Proposal Number(s): 12342

Abstract: Clavulanic acid and avibactam are clinically deployed serine β-lactamase inhibitors, important as a defence against antibacterial resistance. Bicyclic boronates are recently discovered inhibitors of serine and some metallo β-lactamases. Here we show that avibactam and a bicyclic boronate inhibit L2 (serine β-lactamase) but not L1 (metallo β-lactamase) from the extensively drug resistant human pathogen Stenotrophomonas maltophilia. X-ray crystallography revealed that both inhibitors bind L2 by covalent attachment to the nucleophilic serine. Both inhibitors reverse ceftazidime resistance in S. maltophilia because, unlike clavulanic acid, they do not induce L1 production. Ceftazidime/inhibitor resistant mutants hyper-produce L1, but retain aztreonam/inhibitor susceptibility because aztreonam is not an L1 substrate. Importantly, avibactam, but not the bicyclic boronate is deactivated by L1 at a low rate; the utility of avibactam might be compromised by mutations that increase this deactivation rate. These data rationalize the observed clinical efficacy of ceftazidime/avibactam plus aztreonam as combination therapy for S. maltophilia infections and confirm that aztreonam-like β-lactams plus non-classical β-lactamase inhibitors, particularly avibactam-like and bicyclic boronate compounds, have potential for treating infections caused by this most intractable of drug resistant pathogens.

Journal Keywords: antibiotic resistance; proteomics; enzyme inhibition

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography