The Assemblage of Covalent and Metal Binding Dual Functional Scaffold for Cross-Class Metallo-β-Lactamases Inhibition

Aim: The discovery and development of novel broad-spectrum MβLs inhibitors are urgent to overcome antibiotic resistance mediated by MβLs. Methods & results: 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 Escherichia coli harboring MβLs. 5b 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. Conclusion: The designed compounds can serve as potent broad-spectrum MβLs inhibitors and combat MβLs-producing 'superbug' in combination with β-lactams.