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Predictive Modeling Targets Thymidylate Synthase ThyX in Mycobacterium Tuberculosis | Journal Article / Research | MSF Science Portal
Journal Article
|Research

Predictive Modeling Targets Thymidylate Synthase ThyX in Mycobacterium Tuberculosis

Djaout K, Singh VK, Boum Y II, Katawera V, Becker HF, Bush NG, Hearnshaw SJ, Pritchard JE, Bourbon P, Madrid PB, Maxwell A, Mizrahi V, Myllykallio H, Ekins S
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Abstract
There is an urgent need to identify new treatments for tuberculosis (TB), a major infectious disease caused by Mycobacterium tuberculosis (Mtb), which results in 1.5 million deaths each year. We have targeted two essential enzymes in this organism that are promising for antibacterial therapy and reported to be inhibited by naphthoquinones. ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the human enzyme. DNA gyrase is a DNA topoisomerase present in bacteria and plants but not animals. The current study set out to understand the structure-activity relationships of these targets in Mtb using a combination of cheminformatics and in vitro screening. Here, we report the identification of new Mtb ThyX inhibitors, 2-chloro-3-(4-methanesulfonylpiperazin-1-yl)-1,4-dihydronaphthalene-1,4-dione) and idebenone, which show modest whole-cell activity and appear to act, at least in part, by targeting ThyX in Mtb.

Subject Area

tuberculosis

Languages

English
DOI
10.1038/srep27792
Published Date
10 Jun 2016
PubMed ID
27283217
Journal
Scientific Reports
Volume | Issue | Pages
Volume 6, Issue 1
Issue Date
2016-06-01
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