Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo-β-Lactamase NDM-1

Graphical Abstract

Beating β-lactam beaters: Zinc-binding benzimidazoles and benzoxazoles were investigated for inhibition of the clinically important metallo-β-lactamase NDM-1, which inactivates nearly all β-lactam antibiotics. Several potent inhibitors were identified with IC₅₀ values as low as 0.38 μM. Top compounds restored the susceptibility of NDM-1-expressing E. coli to meropenem. Spectroscopic and molecular docking studies suggest ternary complex formation as the inhibition mechanism.

Abstract

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