2. Academic Validation
  3. Cell permeable vanX inhibitors as vancomycin re-sensitizing agents

Cell permeable vanX inhibitors as vancomycin re-sensitizing agents

  • Bioorg Med Chem Lett. 2014 Jun 1;24(11):2535-8. doi: 10.1016/j.bmcl.2014.03.097.
Ramaiah Muthyala 1,  Namrata Rastogi 2,  Woo Shik Shin 3,  Marnie L Peterson 4,  Yuk Yin Sham 5
Affiliations

Affiliations

  • 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.
PMID: 24751446 DOI: 10.1016/j.bmcl.2014.03.097
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.

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