Dipyridyl-substituted thiosemicarbazone as a potent broad-spectrum inhibitor of metallo-β-lactamases

To combat the superbug infection caused by metallo-?-lactamases (M?Ls), a dipyridyl-substituted thiosemicarbazone (DpC), was identified to be the broad-spectrum inhibitor of M?Ls (NDM-1, VIM-2, IMP-1, ImiS, L1), with an IC50 value in the range of 0.021?1.08 ?M. It reversibly and competitively inhibited NDM-1 with a Ki value of 10.2 nM. DpC showed broad-spectrum antibacterial effect on clinical isolate K. pneumonia, CRE, VRE, CRPA and MRSA, with MIC value ranged from 16 to 32 ?g/mL, and exhibited synergistic antibacterial effect with meropenem on M?Ls-producing bacteria, resulting in a 2?16-, 2?8-, and 8-fold reduction in MIC of meropenem against EC-M?Ls, EC01-EC24, K. pneumonia, respectively. Moreover, mice experiments showed that DpC also had synergistic antibacterial action with meropenem. In this work, DpC was identified to be a potent scaffold for the development of broad-spectrum inhibitors of M beta Ls.

Automated summary

DpC was identified as a potent scaffold for broad-spectrum inhibitors of MβLs, showing good antibacterial effects against multiple bacteria and synergistic action with meropenem.