A weak point of the TB bacillus identified
In a study published in PNAS, scientists reveal that the survival of the bacterium responsible for tuberculosis, Mycobacterium tuberculosis, depends on a specialized transporter that enables it to absorb sulfate, a mineral form of sulfur. This transporter is highly specific to M. tuberculosis and could therefore be a target for drugs without side effects on human cells.
Tuberculosis, still a formidable enemy
Tuberculosis remains one of the deadliest infectious diseases today. Each year, it affects millions of people worldwide and continues to claim many lives, despite the existence of a vaccine and available treatments. In 2023, the World Health Organization reported 10.8 million new cases. The situation is further complicated by the emergence of antibiotic-resistant strains: these bacteria evade current treatments—which are already lengthy and difficult to follow—making the search for new solutions more urgent than ever.
Understanding the bacterium’s lifestyle to fight it more effectively
Tuberculosis is caused by a bacterium known as Mycobacterium tuberculosis. To combat it effectively, it is essential to understand its way of life. How does it survive inside the human body? How does it hijack our immune defenses to its own advantage? And above all, what mechanisms allow it to persist for years in a dormant state before reactivating to cause disease? These are the fundamental questions that a team of French scientists set out to address—leading to a major breakthrough published in the journal PNAS.
A discovery about the bacterium’s sulfur intake
For a long time, the scientific community believed that the bacterium fed mainly on organic sulfur, particularly from methionine, an amino acid taken directly from our cells. But this study overturns that view: the scientists show that M. tuberculosis actually prefers to import “inorganic” sulfate—a form of sulfur present in our bodies—through a specialized transporter named SubI-CysTWA.
To reach this conclusion, they used a highly precise imaging technology called NanoSIMS, which makes it possible to visualize chemical elements—including sulfur—directly within the cells infected by the bacterium. They observed that the bacterium stores large amounts of sulfur derived from sulfate, especially when it is in full activity.
The SubI transporter is required for sulfate import in intracellular bacteria.
The bacteria (M. tuberculosis) were cultured in the presence of glucose labeled with the isotope ¹³C to allow visualization within infected macrophages (left panels). The cells were incubated with sulfate labeled with ³³S in order to track the molecule inside infected cells (right panels). The cells were infected either with wild-type bacteria (top panels) or with a mutant lacking an active SubI transporter (bottom panels). The figure shows sulfate accumulation in the wild-type bacteria, but not in those that do not express the transporter.
© W. Le Mouëllic, F. Levillain, T.-D. Wu.
A weak point to exploit for future treatments
The scientists then inactivated the gene responsible for producing this transporter. The result: the growth of the bacterium in laboratory cultures slowed down, and its survival decreased in the lungs of infected mice. It also became more sensitive to oxidative stress—a natural reaction of our defenses against pathogens.
This dependency is particularly interesting because the SubI-CysTWA transporter exists only in M. tuberculosis. Drugs targeting this mechanism could therefore weaken the bacterium without harming human cells. Such an approach could also boost the effectiveness of antibiotics already in use, such as isoniazid, and help shorten treatment duration.
A promising breakthrough
In a context where current treatments are lengthy and resistance is on the rise, this discovery opens a new avenue: blocking access to sulfate to prevent the bacterium from defending itself. In the long term, this could improve treatment efficacy, limit resistance, and ultimately save many lives.
Reference
Wendy Le Mouëllic, Florence Levillain, Ting-Di Wu, Maxime Caouaille, Philippe Bousso, Yannick Poquet*, Olivier Neyrolles* (2025) Inorganic sulfate is critical for Mycobacterium tuberculosis lung tissue colonization and redox balance. Proc Natl Acad Sci USA DOI: 10.1073/pnas.2503966122
Contact Scientist
Olivier Neyrolles | Olivier.Neyrolles@ipbs.fr
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Françoise Viala | Communication@ipbs.fr