The bacteria that cause tuberculosis (TB) may have an “on-off switch” that lets them pause and restart growth, according to a new study from the University of Surrey and the University of Oxford. The research helps explain why TB is so hard to treat with antibiotics and could pave the way for better drugs.

In a study published in The EMBO Journal, researchers show how Mycobacterium tuberculosis uses a reversible process called ADP-ribosylation to modify its DNA and control both replication and gene activity. It is the first time this kind of DNA modification has been shown to regulate key processes like gene expression and DNA copying in any organism.

Professor Graham Stewart, co-author of the study from the University of Surrey, said:

“We’ve found a way that Mycobacterium tuberculosis can slow down its growth and potentially allow it to hide from the immune response and resist antibiotics. By showing that ADP-ribosylation of DNA can control both replication and gene expression, we’ve discovered a new layer of regulation that could be key to understanding TB’s persistence. If we can target this process, we could make the bacteria easier to eliminate – especially in the slow-growing or dormant states that current treatments struggle to reach.”

The study focused on two enzymes: DarT, which adds the ADP-ribose tag to DNA, and DarG, which removes it. When DarT is active, it stops the bacteria from copying their DNA and dividing. When DarG removes the tag, growth resumes. This start-and-stop control may help the bacteria survive in harsh conditions, making them more resilient during long-term infections.

To find out more about how this molecular switch works, the researchers used a CRISPR interference (CRISPRi) system to selectively reduce levels of DarG. This allowed DarT to act without restraint, leading to the build-up of DNA modifications and halting bacterial growth. The team then used a technique called ADPr-Seq to map where these tags appeared across the genome, alongside live-cell imaging and RNA sequencing to track changes in DNA replication, cell division and gene expression. These tools helped reveal how ADP-ribosylation affects both the ability of the bacteria to replicate and the activity of genes needed for survival in stressful environments.

According to the World Health Organization, TB kills 1.25 million people globally every year. In 2023, around 10.8 million people fell ill with the disease.