AUTHOR=Wescott Heather H. , Zuniga Edison S. , Bajpai Anumita , Trujillo Carolina , Ehrt Sabine , Schnappinger Dirk , Roberts David M. , Parish Tanya 

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

JOURNAL=Frontiers in Microbiology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.02542

DOI=10.3389/fmicb.2018.02542

ISSN=1664-302X

ABSTRACT=Tuberculosis is a massive global disease 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 good activity against Mycobacterium tuberculosis. 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 could be achieved, it would represent an attractive target for M. tuberculosis drug discovery and development efforts.