The assemblage of covalent and metal binding dual functional scaffold for cross-class metallo-β-lactamases inhibition

The discovery and development of novel broad-spectrum MβLs inhibitors are urgent to overcome antibiotic resistance mediated by MβLs. Herein, the synthesized 21 compounds exhibited potent inhibition to the clinically important MβLs (NDM-1, IMP-1 and ImiS) and effectively restored the antibacterial efficacy of cefazolin and imipenem against harboring MβLs. was first identified to be dual functional broad-spectrum MβLs inhibitor through assemblage of covalent and metal binding scaffold, which irreversibly inhibited B1, B2 MβLs via forming a Se–S covalent bond, and competitively inhibited B3 MβLs by coordinating the metals at active site. The designed compounds can serve as potent broad-spectrum MβLs inhibitors and combat MβLs-producing ‘superbug’ in combination with β-lactams. The discovery of dual functional broad-spectrum MβLs inhibitor through assemblage of covalent and metal binding scaffold.