Researchers at the Institute of Mathematical Sciences (IMSc) and the Indian Institute of Science (IISc) have discovered an intriguing mechanism by which the bacteria that causes tuberculosis defends itself against dangerous foreign DNA. Their research shows how Mycobacterium tuberculosis (Mtb) meticulously controls its genes to adapt and live. This finding broadens our knowledge of the biology of the bacteria and creates new avenues for the development of more potent and efficient TB medicines.
The study centres on a protein called Lsr2, a small but powerful molecule in Mycobacterium that acts as a regulatory protein and is involved in several key cellular processes, including forming the bacterium’s cell wall and resisting antibiotics. Lsr2 acts as a master regulator inside the TB bacterium. Lsr2 helps the organism survive by controlling the activity of many genes across its genome. Researchers believe that interfering with this protein could weaken the bacterium, making it easier to destroy.
“This protein is interesting to study because it controls a large set of genes in the bacteria,” said Mahipal Ganji, Assistant Professor at the Department of Biochemistry, IISc, and the corresponding author of the study.
Bacteria such as M. tuberculosis can obtain foreign DNA over time, often through viruses that insert their genetic material into the bacterial genome.
While some of these genetic additions may be harmless, others can significantly disrupt the bacterium’s normal functions. When these foreign genes become active, they can produce proteins that interfere with the vital process the cell depends on to survive and multiply. To protect itself from such harmful effects, the bacterium must be able to accurately identify and silence any unwanted or potentially harmful DNA.
The researchers found that Lsr2 plays an important role in this defence system, selectively switching off the parts of the genome that contain foreign genetic material, allowing the bacterium to maintain normal function. In most organisms, gene-regulating proteins work by attaching to specific DNA sequences, preventing the cell’s machinery from reading and acting on that genetic code.
The IISc–IMSc team found that Lsr2 binds to large DNA regions that are rich in the bases adenine (A) and thymine (T). These AT-rich stretches are commonly linked with foreign DNA. What surprised the scientists was what happened next. When several Lsr2 proteins bind close to one another, they begin to cluster together, forming dense structures known as condensates. This clumping physically blocks the DNA, preventing it from being transcribed into proteins.
“This was completely unexpected,” said Ganji. We were initially doing single-molecule experiments and noticed signs that Lsr2 might be forming condensates. That observation sparked our curiosity and led us to dig deeper into the phenomenon. The researchers discovered that this condensation acts like a protective shield for the bacterium, effectively silencing harmful genes. By blocking the expression of foreign DNA, Lsr2 makes sure that only the bacterium’s own essential genes stay active. Keeping it safe and functioning normally.
The study also builds on earlier work by the team, which showed that Lsr2 is essential for M. tuberculosis to successfully infect its host. Taken together, these findings underline just how important this protein is to the bacterium’s survival and its ability to cause disease. Because Lsr2 is important to many of the vital processes, it stands out as a promising target for new anti-TB drugs. If researchers can develop compounds that prevent Lsr2 from binding to DNA or forming clusters, they could disrupt the bacterium’s internal control system.
By uncovering an unusual and highly effective way of gene-silencing mechanism, the IISc–IMSc study adds an important piece to the puzzle of how Mycobacterium tuberculosis survives and expands. Researchers believe that gaining a deeper understanding of these molecular processes could potentially lead to the development of new and more effective strategies to combat tuberculosis.
