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

Publication ,  Journal Article
Jackson, AC; Pinter, TBJ; Talley, DC; Baker-Agha, A; Patel, D; Smith, PJ; Franz, KJ
Published in: ChemMedChem
February 2021

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.

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Published In

ChemMedChem

DOI

EISSN

1860-7187

ISSN

1860-7179

Publication Date

February 2021

Volume

16

Issue

4

Start / End Page

654 / 661

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

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Jackson, A. C., Pinter, T. B. J., Talley, D. C., Baker-Agha, A., Patel, D., Smith, P. J., & Franz, K. J. (2021). Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo-β-Lactamase NDM-1. ChemMedChem, 16(4), 654–661. https://doi.org/10.1002/cmdc.202000607
Jackson, Abigail C., Tyler B. J. Pinter, Daniel C. Talley, Adnan Baker-Agha, Dhruvil Patel, Paul J. Smith, and Katherine J. Franz. “Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo-β-Lactamase NDM-1.ChemMedChem 16, no. 4 (February 2021): 654–61. https://doi.org/10.1002/cmdc.202000607.
Jackson AC, Pinter TBJ, Talley DC, Baker-Agha A, Patel D, Smith PJ, et al. Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo-β-Lactamase NDM-1. ChemMedChem. 2021 Feb;16(4):654–61.
Jackson, Abigail C., et al. “Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo-β-Lactamase NDM-1.ChemMedChem, vol. 16, no. 4, Feb. 2021, pp. 654–61. Epmc, doi:10.1002/cmdc.202000607.
Jackson AC, Pinter TBJ, Talley DC, Baker-Agha A, Patel D, Smith PJ, Franz KJ. Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo-β-Lactamase NDM-1. ChemMedChem. 2021 Feb;16(4):654–661.
Journal cover image

Published In

ChemMedChem

DOI

EISSN

1860-7187

ISSN

1860-7179

Publication Date

February 2021

Volume

16

Issue

4

Start / End Page

654 / 661

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