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Broad spectrum β-lactamase inhibition by a thioether substituted bicyclic boronate

DOI: 10.1021/acsinfecdis.9b00330 DOI Help

Authors: Anete Parkova (Latvian Institute of Organic Synthesis) , Anka Lucic (University of Oxford) , Alen Krajnc (University of Oxford) , Jurgen Brem (University of Oxford) , Karina Calvopina (University of Oxford) , Gareth Langley (University of Oxford) , Michael A. Mcdonough (University of Oxford) , Peteris Trapencieris (Latvian Institute of Organic Synthesis) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: December 2019

Abstract: β-Lactamases comprise the most important known mode of resistance to β-lactam antibiotics. Boronic acids/boronate esters show promise as a new class of β-lactamase inhibitors with the potential to inhibit both the metallo- and serine-β-lactamases. We report studies employing representative β-lactamases concerning a bicyclic boronate ester with a thioether rather than the more typical β-lactam antibiotic ‘C-6/C-7’ acylamino side chain as present in the penicillin/cephalosporin antibiotics. The results, including a crystal structure of the clinically relevant VIM-2 metallo β-lactamase in complex with the inhibitor, reveal the potential of boronate inhibitors without the canonical acylamino side chain for inhibition of a broader range of serine- and metallo- β-lactamases compared to previous bicyclic boronates, including the metallo-β-lactamase L1. They imply further SAR studies will expand the already broad scope of -lactamase inhibition by bicyclic boronates.

Journal Keywords: βeta-lactam antibiotic resistance; boronate/boron based β-lactamase/hydrolase inhibitors; serine β-lactamase; metallo β-lactamase; carbapenem/penicillin/cephalosporin

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography