Identification of Enolase as the Target of 2-Aminothiazoles in Mycobacterium tuberculosis

• Published in: Frontiers in microbiology Vol. 9; p. 2542
• Main Authors: Wescott, Heather H, Zuniga, Edison S, Bajpai, Anumita, Trujillo, Carolina, Ehrt, Sabine, Schnappinger, Dirk, Roberts, David M, Parish, Tanya
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 26-10-2018
• Subjects: anti-bacterial activity; anti-tubercular; drug target; drug target discovery; glycolysis; Microbiology; tuberculosis; anti-tubercular; anti-bacterial activity; drug target discovery; drug target; glycolysis; tuberculosis
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2018.02542

Tuberculosis is a massive global burden and
is increasingly resistant to first- and second-line drugs. There is an acute need for new anti-mycobacterial drugs with novel targets. We previously evaluated a series of 2-aminothiazoles with activity against
. In this study, we identify the glycolytic enzyme enolase as the target of these molecules using pull down studies. We demonstrate that modulation of the level of enolase expression affects sensitivity to 2-aminothiazoles; increased expression leads to resistance while decreased protein levels increase sensitivity. Exposure to 2-aminothiazoles results in increased levels of metabolites preceding the action of enolase in the glycolytic pathway and decreased ATP levels. We demonstrate that 2-aminothiazoles inhibit the activity of the human α-enolase, which could also account for the cytotoxicity of some of those molecules. If selectivity for the bacterial enzyme over the human enzyme could be achieved, enolase would represent an attractive target for
drug discovery and development efforts.