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

Autor: Jackson AC; Department of Chemistry, Duke University, Durham, NC 27708, USA., Pinter TBJ; Department of Chemistry, Duke University, Durham, NC 27708, USA., Talley DC; Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA., Baker-Agha A; Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA., Patel D; Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA., Smith PJ; Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA., Franz KJ; Department of Chemistry, Duke University, Durham, NC 27708, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2021 Feb 17; Vol. 16 (4), pp. 654-661. Date of Electronic Publication: 2020 Nov 19.
DOI: 10.1002/cmdc.202000607
Abstrakt: 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 IC 50 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.
(© 2020 Wiley-VCH GmbH.)
Databáze: MEDLINE
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