Will morphing boron-based inhibitors beat the beta-lactamases?

摘要

The beta-lecterns remain the most important antibacterials, but their use is increasingly compromised by resistance, importantly by beta-lactamases. Although beta-lactam and non-p-lactam inhibitors forming stable acyl-enzyme complexes with nucleophilic serine beta-lactamases (SBLs) are widely used, these are increasingly susceptible to evolved SBLs and do not inhibit metallo-beta-lactamases (MBLs). Boronic acids and boronate esters, especially cyclic ones, can potently inhibit both SBLs and MBLs. Vaborbactam, a monocyclic boronate, is approved for clinical use, but its beta-lactamase coverage is limited. Bicyclic boronates rapidly react with SBLs and MBLs forming stable enzyme inhibitor complexes that mimic the common anionic high-energy tetrahedral intermediates in SBL/MBL catalysis, as revealed by crystallography. The ability of boronic acids to 'morph' between sp(2) and sp(3) hybridisation states may help enable potent inhibition. There is limited structure-activity relationship information on the (bi)cyclic boronate inhibitors compared to beta-lecterns, hence scope for creativity towards new boron-based beta-lactamase inhibitors/antibacterials.