Cell permeable vanX inhibitors as vancomycin re-sensitizing agents

Ramaiah Muthyala; Namrata Rastogi; Woo Shik Shin; Marnie L Peterson; Yuk Yin Sham

doi:10.1016/j.bmcl.2014.03.097

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. Epub 2014 Apr 8.

Authors

Ramaiah Muthyala¹, Namrata Rastogi², Woo Shik Shin³, Marnie L Peterson⁴, Yuk Yin Sham⁵

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Cell Membrane Permeability / drug effects*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HEK293 Cells
Humans
Hydroxamic Acids / chemistry
Molecular Structure
Serine-Type D-Ala-D-Ala Carboxypeptidase / antagonists & inhibitors*
Serine-Type D-Ala-D-Ala Carboxypeptidase / metabolism
Structure-Activity Relationship
Vancomycin / chemical synthesis
Vancomycin / chemistry
Vancomycin / pharmacology*

Substances

Bacterial Proteins
Enzyme Inhibitors
Hydroxamic Acids
Vancomycin
Serine-Type D-Ala-D-Ala Carboxypeptidase
VanX dipeptidase