Identification and Validation Novel of VIM-2 Metallo-β-lactamase Tripeptide Inhibitors.

The development of novel inhibitors against metallo-β-lactamase is essential to remedy metallo-β-lactamase mediated bacterial resistance. A recently emerged metallo-β-lactamase, VIM-2, has demonstrated resistance to existing β-lactamase inhibitors in the clinic. In this study, a hybrid virtual screening protocol that combines pharmacophore modeling, molecular docking, and calculation of binding free energy was employed to screen an internal tripeptide database for novel inhibitors against VIM-2. This resulted in four tripeptides (WWC, WCW, MCW, YCW) as potential inhibitors, and their effects on VIM-2 metallo-β-lactamase were subsequently tested in vitro. Significantly, two peptides (MCW, YCW) exhibited potent inhibitory activities with IC50 values of 18.15 µM and 52.9 µM, respectively. To our knowledge, this is the first study that employed the hybrid virtual screening of combinational peptide database and discovered potent peptide inhibitors of VIM-2 metallo-β-lactamase.