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Bioorg Med Chem Lett. 2014 Jun 1;24(11):2535-8. doi: 10.1016/j.bmcl.2014.03.097. Epub 2014 Apr 8.

Cell permeable vanX inhibitors as vancomycin re-sensitizing agents.

Author information

1
Center for Orphan Drug Research, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States; Department of Experimental & Clinical Pharmacology, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States. Electronic address: muthy003@umn.edu.
2
Center for Orphan Drug Research, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States; Department of Experimental & Clinical Pharmacology, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States.
3
Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, United States.
4
Department of Experimental & Clinical Pharmacology, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States.
5
Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, United States. Electronic address: shamx002@umn.edu.

Abstract

VanX is an induced zinc metallo d-Ala-d-Ala dipeptidase involved in the viable remodeling of bacterial cell wall that is essential for the development of VREF. Here we report two cyclic thiohydroxamic acid-based peptide analogs that were designed, synthesized and investigated as vancomycin re-sensitizing agents. These compounds exhibit low micromolar inhibitory activity against vanX, with low cytotoxicity and were shown to increase vancomycin sensitivity against VREF. The improved pharmacological properties of these novel inhibitors over previous transition state mimics should provide an enhanced platform for designing potent vanX inhibitors for overcoming vancomycin resistance.

KEYWORDS:

Antibiotics; Drug resistance; Pyrithione; Thiohydroxamic acid; VanX; Vancomycin

PMID:
24751446
DOI:
10.1016/j.bmcl.2014.03.097
[Indexed for MEDLINE]
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