Tuberculosis succumbs to a new strategy

Tuberculosis (TB) succumbs to a new strategy.

In 2023, approximately 10.8 million people contracted TB, resulting in 1.25 million deaths, according to the World Health Organization. Scientists have reported a new compound, known as JNJ-6640, that uses a new strategy to kill Mycobacterium tuberculosis, the bacterium causing TB. This discovery could strengthen the arsenal of drugs fighting TB, which are constantly threatened by the development of resistance in M. tuberculosis.

The development of JNJ-6640 resulted from a collaborative effort between scientists at Johnson & Johnson, the London School of Hygiene and Tropical Medicine, and other partners. The molecule inhibits amidophosphoribosyltransferase, known as PurF, which is essential for making purines. By stopping the synthesis of purines, JNJ-6640 prevents the production of essential building blocks for the bacterium, leading to its death.

A New Approach to Fighting TB

Scientists initially believed that targeting de novo purine biosynthesis would not be effective against M. tuberculosis because the bacterium can recycle purines. However, lung tissue samples revealed insufficient purines to sustain the rescue process. JNJ-6640 is highly selective for PurF in M. tuberculosis, despite the presence of a human pathway for de novo purine biosynthesis.

The research, which was supported by the Gates Foundation’s Tuberculosis Drug Accelerator, "opens up a whole new area of drug discovery possibilities for TB and maybe for other bacteria as well,” according to Dirk A. Lamprecht, a researcher at the University of Cape Town’s Holistic Drug Discovery and Development Centre (H3D). JNJ-6640 was effective in fighting TB in mice when combined with the TB-fighting drugs bedaquiline and pretomanid.

The goal is to replace linezolid, a drug in TB-fighting cocktails, to reduce toxic side effects. Carl F. Nathan of Weill Cornell Medical College noted that there is still a long way to go before PurF inhibitors are incorporated into TB treatment. JNJ-6640's poor metabolic stability and limited solubility present challenges, according to Nathan.

Richard J. Wall of the London School of Hygiene and Tropical Medicine noted that any drug candidate will need to address JNJ-6640’s metabolic instability. Lamprecht says that H3D is developing new PurF inhibitors that could become drug candidates.