The Ergothioneine Link
Using novel technologies, KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH) scientists have made an important step forward in better understanding how the bacteria that causes tuberculosis, Mycobacterium tuberculosis (Mtb), survives in a hostile environment in the lungs.
Using metabolomics K-RITH Investigator and University of Alabama at Birmingham (UAB) Professor of Microbiology, Adrie Steyn, together with UAB Instructor Vikram Saini and K-RITH Research Associate Dr Bridgette Cumming have further characterised the small Mtb protein called WhiB3. They have discovered that WhiB3 and the metabolite, ergothioneine, are linked and that ergothioneine is essential for the survival of Mtb in mice. In a paper published in the academic journal Cell Reports they show how WhiB3 regulates ergothioneine, which in turn helps to maintain the redox balance and bioenergetic homeostasis in the Mtb cells that is required for them to survive.
Both redox and bioenergetic homeostasis determine how effective anti-TB drugs are. Testing the new generation anti-TB drug bedaquiline, as well as other frontline drugs on “mutant” Mtb strains, which are unable to produce ergothioneine, they have observed clear trends to indicate that ergothioneine plays a role in Mtb drug susceptibility. They have also found that ergothioneine, and therefore by extension redox homeostasis, is necessary for maintaining Mtb’s virulence; its ability to establish an infection in its host.
Their findings could begin to explain why some people respond to TB drugs, and why others don’t – as well as pointing to a potential drug therapy target. ‘If we can cause an imbalance in the redox homeostasis in the mycobacterium then it cannot produce energy for the bacterium to survive,’ explains co-first author Dr Cumming. ‘So if we can prevent ergothioneine from being formed, the bacteria will be more susceptible to anti-TB drugs. Also, Mtb may then be potentially more susceptible to any oxidative stress induced by the cells of the immune system.’
The scientists adapted technology usually used to study the health of cells in cancer, Alzheimer’s, and diabetes for this research. It is the first time that the Seahorse Biosciences Metabolic Flux Analyser has been used to study Mtb.
‘Without exploiting this new technology, we wouldn’t have made these discoveries,’ says Dr Steyn.
‘Applying this technology was crucial to studying TB bioenergetics and redox homeostasis and combining that with metabolomics, which has ultimately led us to our major claims that bioenergetic and redox homeostasis is necessary for anti-mycobacterial drug efficacy, and also for TB virulence.’
‘As science progresses, sometimes you hit a brick wall and you have to take two steps back and say ‘OK – if we can’t answer this question, how can we modify technology to allow us to answer it?’,’ he added. ‘It’s the first demonstration of linking bioenergetics with redox homeostasis to help potentially explain two things: why Mtb is drug resistant, and the mechanism by which Mtb causes disease. That connection hasn’t been described before, because there was a lack of tools to do it. We have the tools here at K-RITH, and that allowed us to make these discoveries.’
*Click here to read the paper, titled “Ergothioneine Maintains Redox and Bioenergetic Homeostasis Essential for Drug Susceptibility and Virulence of Mycobacterium tuberculosis”.