Abstract
Tuberculosis is a massive global burden and Mycobacterium tuberculosis 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 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 for the bacterial enzyme over the human enzyme could be achieved, enolase would represent an attractive target for M. tuberculosis drug discovery and development efforts.
Highlights
Tuberculosis (TB) remains a deadly global disease and continues to be one of the leading causes of death worldwide (WHO, 2017)
We were interested in determining the target of a promising series of 2-ATs with potent activity against M. tuberculosis
We chose to use cell extracts from M. smegmatis for our affinity binding assays since 2-AT compounds are active against this organism (Kesicki et al, 2016) and we reasoned that the target in M. smegmatis and M. tuberculosis was likely to be conserved
Summary
Tuberculosis (TB) remains a deadly global disease and continues to be one of the leading causes of death worldwide (WHO, 2017). There has been a renewed effort in recent years to develop new vaccine and treatment candidates for TB. With the emergence of both multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, this regimen is becoming increasingly ineffective. Treating MDR and XDR strains of M. tuberculosis is very difficult, requiring therapeutic regimens lasting up to 2 years and consisting of more toxic and costly second- and third-line drugs, with often limited success. The discovery and development of new TB drugs with novel mechanisms of action is crucial to our ability to fight this increasing global health threat
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