Structure-based design of covalent inhibitors targeting metallo-β-lactamases

The emergence and prevalence of metallo-beta-lactamases (M beta Ls)-mediated bacterial resistance has seriously threatened the global health today. M beta Ls are deemed to be one of the most worrying bacterial resistance factors that hydrolyze nearly all beta-lactam antibiotics. However, none of M beta L inhibitors have appeared in clinic to date. This review surveys the common covalent targets in B1 and B2 M beta Ls, summarizes all covalent inhibitors of M beta Ls and their inhibition modes as of 2020, highlights the importance of the rational design of covalent M beta L inhibitor guided by the crystal structure and the development of dual-action covalent M beta L/S beta L inhibitors based on lysine residue of M beta Ls and serine residue of S beta Ls, and describes the approaches to discern the covalent inhibition mechanism to guide the development of future therapeutics. (C) 2020 Elsevier Masson SAS. All rights reserved.