New Drug Target Identified to Combat Drug-Resistant Tuberculosis

Researchers have identified a new drug target to combat drug-resistant tuberculosis, a development published in Nature that could lead to alternative treatments for one of the world’s deadliest infectious diseases, according to findings from Imperial and the London School of Hygiene & Tropical Medicine.

Tuberculosis remains among the top ten causes of death worldwide and one of the three largest killers among infectious diseases, causing over 1.25 million deaths in 2023. Because the bacteria that cause the illness, Mycobacterium tuberculosis, are difficult for antibiotics to reach, patients require long treatment courses involving multiple drugs. Side effects frequently cause patients to stop treatment early, creating selective pressure for drug-resistant strains to evolve and spread.

Inhibiting the PurF Enzyme

In a collaboration involving pharmaceutical company Janssen Pharmaceutica—now known as Johnson & Johnson Innovative Medicine—researchers screened thousands of chemical compounds to identify agents capable of killing the bacteria. The team discovered that a molecule called JNJ-6640 successfully stops the bacteria from replicating. According to Dr. William Pearson at the London School of Hygiene & Tropical Medicine, researchers found a compound that proved incredibly potent against tuberculosis.

Through genetic analysis, protein studies, and microscopy, the research team determined that these compounds work by inhibiting an enzyme inside the bacteria known as PurF. Mycobacterium tuberculosis uses the PurF enzyme to synthesize purines, which are molecules essential for cellular functions such as metabolism and signaling. While some bacteria survive by scavenging purines from a host organism, tests using lung tissue samples from humans and mice showed that tuberculosis bacteria could not recover enough purines this way to survive.

Animal Trials and Research Funding

Following the laboratory discoveries, the team conducted in vivo trials using animal models, which demonstrated that JNJ-6640 effectively reduces tuberculosis infection in mice. However, Dr. Gerald Larrouy-Maumus in Imperial’s Department of Life Sciences noted that tuberculosis continues to be an under-recognized problem even in the UK, disproportionately impacting low- and middle-income countries and demanding radical new approaches.

Although JNJ-6640 lacks the stability required for ingestion as a viable drug candidate, identifying the PurF enzyme as an effective target provides a novel strategy for developing future treatments. The research received funding from Janssen Pharmaceutica, the Bill and Melinda Gates Foundation, and Wellcome, alongside analytical support from the Agilent Measurement Suite at Imperial’s White City Campus. Drug development experts around the world can now access the published findings to optimize compounds against this newly identified target.