
Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo-β-Lactamase NDM-1.
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.
Duke Scholars
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Related Subject Headings
- beta-Lactamases
- Zinc
- Structure-Activity Relationship
- Molecular Structure
- Microbial Sensitivity Tests
- Medicinal & Biomolecular Chemistry
- Escherichia coli
- Enzyme Inhibitors
- Dose-Response Relationship, Drug
- Chelating Agents
Citation

Published In
DOI
EISSN
ISSN
Publication Date
Volume
Issue
Start / End Page
Related Subject Headings
- beta-Lactamases
- Zinc
- Structure-Activity Relationship
- Molecular Structure
- Microbial Sensitivity Tests
- Medicinal & Biomolecular Chemistry
- Escherichia coli
- Enzyme Inhibitors
- Dose-Response Relationship, Drug
- Chelating Agents