Structure-Based Development of (1-(3′-Mercaptopropanamido)­methyl)­boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- and Serine-β-lactamases

The emergence and spread of bacterial
pathogens acquired metallo-β-lactamase
(MBL) and serine-β-lactamase (SBL) medicated β-lactam
resistance gives rise to an urgent need for the development of new
dual-action MBL/SBL inhibitors. Application of a pharmacophore fusion
strategy led to the identification of (2′S)-(1-(3′-mercapto-2′-methylpropanamido)­methyl)­boronic
acid (MS01) as a new dual-action inhibitor, which manifests
broad-spectrum inhibition to representative MBL/SBL enzymes, including
the widespread VIM-2 and KPC-2. Guided by the VIM-2:MS01 and KPC-2:MS01 complex structures, further structural
optimization yielded new, more potent dual-action inhibitors. Selectivity
studies indicated that the inhibitors had no apparent inhibition to
human angiotensin-converting enzyme-2 and showed selectivity across
serine hydrolyases in E. coli and human HEK293T cells
labeled by the activity-based probe TAMRA-FP. Moreover, the inhibitors
displayed potentiation of meropenem efficacy against MBL- or SBL-positive
clinical isolates without apparent cytotoxicity. This work will aid
efforts to develop new types of clinically useful dual-action inhibitors
targeting MBL/SBL enzymes.