Benzimidazole And Benzoxazole Zinc Chelators As Inhibitors Of Metallo-Beta-Lactamase Ndm-1

Bacterial expression of beta-lactamases, which hydrolyze beta-lactam antibiotics, contributes to the growing threat of antibacterial drug resistance. Metallo-beta-lactamases, such as NDM-1, use catalytic zinc ions in their active sites and hydrolyze nearly all clinically available beta-lactam antibiotics. Inhibitors of metallo-beta-lactamases are urgently needed to overcome this resistance mechanism. Zinc-binding compounds are promising leads for inhibitor development, as many NDM-1 inhibitors contain zinc-binding pharmacophores. Here, we evaluated 13 chelating agents containing benzimidazole and benzoxazole scaffolds as NDM-1 inhibitors. Six of the compounds showed potent inhibitory activity with IC50 values as low as 0.38 mu M, and several compounds restored the meropenem susceptibility of NDM-1-expressing E. coli. Spectroscopic and docking studies suggest ternary complex formation as the mechanism of inhibition, making these compounds promising for development as NDM-1 inhibitors.