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

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

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2535-2538
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2014.03.097
State	Published - Jun 1 2014

Bibliographical note

Funding Information:
We thank Prof. Christopher Walsh for providing the plasmid used in the expression of vanX. This research was supported by the faculty development grant from the University of Minnesota Academic Health Center . We thank the University of Minnesota Supercomputing Institute and the Center for Drug Design for providing the necessary computational and instrumentation resources. We thank Dr. Fred Schendel, Biotechnology Institute, University of Minnesota for vanX protein preparation. We also thank Jesse Meyer for performing the biochemical assays.

Keywords

Antibiotics
Drug resistance
Pyrithione
Thiohydroxamic acid
VanX
Vancomycin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Cell permeable vanX inhibitors as vancomycin re-sensitizing agents",

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.",

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author = "Ramaiah Muthyala and Namrata Rastogi and Shin, {Woo Shik} and Peterson, {Marnie L.} and Sham, {Yuk Yin}",

note = "Funding Information: We thank Prof. Christopher Walsh for providing the plasmid used in the expression of vanX. This research was supported by the faculty development grant from the University of Minnesota Academic Health Center . We thank the University of Minnesota Supercomputing Institute and the Center for Drug Design for providing the necessary computational and instrumentation resources. We thank Dr. Fred Schendel, Biotechnology Institute, University of Minnesota for vanX protein preparation. We also thank Jesse Meyer for performing the biochemical assays. ",

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AU - Rastogi, Namrata

AU - Shin, Woo Shik

AU - Peterson, Marnie L.

AU - Sham, Yuk Yin

N1 - Funding Information: We thank Prof. Christopher Walsh for providing the plasmid used in the expression of vanX. This research was supported by the faculty development grant from the University of Minnesota Academic Health Center . We thank the University of Minnesota Supercomputing Institute and the Center for Drug Design for providing the necessary computational and instrumentation resources. We thank Dr. Fred Schendel, Biotechnology Institute, University of Minnesota for vanX protein preparation. We also thank Jesse Meyer for performing the biochemical assays.

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AB - 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.

KW - Antibiotics

KW - Drug resistance

KW - Pyrithione

KW - Thiohydroxamic acid

KW - VanX

KW - Vancomycin

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Cell permeable vanX inhibitors as vancomycin re-sensitizing agents

Abstract

Bibliographical note

Keywords

UN SDGs

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