Broad Spectrum β-Lactamase Inhibition by a Thioether Substituted Bicyclic Boronate.

β-Lactamases comprise the most widely used mode of resistance to β-lactam antibiotics. Cyclic boronates have shown promise as a new class of β-lactamase inhibitor, with pioneering potential to potently inhibit both metallo- and serine-β-lactamases. We report studies concerning a bicyclic boronate ester with a thioether rather than the more typical β-lactam antibiotic "C-6/C-7" acylamino type side chain, which is present in the penicillin/cephalosporin antibiotics. The thioether bicyclic boronate ester was tested for activity against representative serine- and metallo-β-lactamases. The results support the broad inhibition potential of bicyclic boronate based inhibitors with different side chains, including against metallo-β-lactamases from B1, B2, and B3 subclasses. Combined with previous crystallographic studies, analysis of a crystal structure of the thioether inhibitor with the clinically relevant VIM-2 metallo-β-lactamase implies that further SAR work will expand the already broad scope of β-lactamase inhibition by bicyclic boronates.