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 M beta Ls inhibitors are urgent to overcome antibiotic resistance mediated by M beta Ls. Methods & results: Herein, the synthesized 21 compounds exhibited potent inhibition to the clinically important M beta Ls (NDM-1, IMP-1 and ImiS) and effectively restored the antibacterial efficacy of cefazolin and imipenem against Escherichia coli harboring M beta Ls. 5b was first identified to be dual functional broad-spectrumM beta Ls inhibitor through assemblage of covalent and metal binding scaffold, which irreversibly inhibited B1, B2 M beta Ls via forming a Se-S covalent bond, and competitively inhibited B3 M beta Ls by coordinating the metals at active site. Conclusion: The designed compounds can serve as potent broad-spectrum M beta Ls inhibitors and combat M beta Ls-producing 'superbug' in combination with beta-lactams. [GRAPHICS] The discovery of dual functional broad-spectrum M beta Ls inhibitor through assemblage of covalent and metal binding scaffold.