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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Jackson, AC; Pinter, TBJ; Talley, DC; Baker-Agha, A; Patel, D; Smith, PJ; Franz, KJ

Published Date

  • February 2021

Published In

Volume / Issue

  • 16 / 4

Start / End Page

  • 654 - 661

PubMed ID

  • 33211374

Pubmed Central ID

  • PMC8114186

Electronic International Standard Serial Number (EISSN)

  • 1860-7187

International Standard Serial Number (ISSN)

  • 1860-7179

Digital Object Identifier (DOI)

  • 10.1002/cmdc.202000607

Language

  • eng