Tuberculosis succumbs to a new strategy

Tuberculosis (TB) is the world’s deadliest infectious disease. In 2023, about 10.8 million people contracted TB, and 1.25 million people died from it, according to the World Health Organization. Scientists from the pharmaceutical industry and public health organizations now report a compound, known as JNJ-6640, that uses a new strategy to kill Mycobacterium tuberculosis, the bacterium that causes TB (Nature 2025, DOI: 10.1038/s41586-025-09177-7).

The discovery could bolster the arsenal of TB-fighting drugs, which are constantly under threat of becoming ineffective as M. tuberculosis develops resistance to them. The last TB-fighting drug to be approved by the US Food and Drug Administration was pretomanid in 2019.

JNJ-6640 resulted from a collaboration between scientists at the pharmaceutical company Johnson & Johnson and the London School of Hygiene and Tropical Medicine and grew to include many other partners. The molecule inhibits the amidophosphoribosyltransferase known as PurF, which is key to making purines from scratch. This class of heterocycles is essential for all forms of life on Earth, and stopping their synthesis in M. tuberculosis prevents production of building blocks for nucleic acids, energy-carrying compounds, and signaling molecules. Without the ability to make purines, the bacterium dies.

Scientists had thought that targeting de novo purine biosynthesis wouldn’t be an effective way to fight M. tuberculosis, because the bacterium can also rescue and recycle purines. But when the researchers examined lung tissue samples, they found there were not enough purines present for the rescue process to sustain the bacterium.

The work “opens up a whole new area of drug discovery possibilities for TB and maybe for other bacteria as well,” says Dirk A. Lamprecht, a researcher at the University of Cape Town’s Holistic Drug Discovery and Development Centre (H3D) who led the project with Anil Koul of the London School of Hygiene and Tropical Medicine. Both Lamprecht and Koul worked at Johnson & Johnson when the project began.

Although there is a human pathway for de novo purine biosynthesis, JNJ-6640 is highly selective for PurF in M. tuberculosis. The researchers also found that JNJ-6640 was able to fight TB in mice when given in combination with the TB-fighting drugs bedaquiline and pretomanid. Koul says the goal is to replace linezolid, a third drug used in TB-fighting cocktails that often has toxic side effects.

Carl F. Nathan, who studies TB at Weill Cornell Medical College and was not involved in the study, says it illustrates the value of the Gates Foundation’s Tuberculosis Drug Accelerator, which helped support the research, as well as what a highly collaborative effort can accomplish. But, he says in an email, “there is still a long way to go before PurF inhibitors are likely to join a TB treatment regimen.” He cites several problems, including JNJ-6640's poor metabolic stability and limited solubility.

Richard J. Wall, a scientist at the London School of Hygiene and Tropical Medicine who also worked on the project, says JNJ-6640's metabolic instability will have to be addressed in any molecule that’s developed as a drug candidate. To that end, Lamprecht says H3D is working to create new PurF inhibitors that could be drug candidates.