ABSTRACT
Bacterial expression of ß-lactamases, which hydrolyze ß-lactam antibiotics, contributes to the growing threat of antibacterial drug resistance. Metallo-ß-lactamases, such as NDM-1, use catalytic zinc ions in their active sites and hydrolyze nearly all clinically available ß-lactam antibiotics. Inhibitors of metallo-ß-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 0.38â µM, 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.
