Mumbai, July 9 -- A newly identified drug candidate, JNJ-6640, has demonstrated a novel mechanism of action against mycobacterium tuberculosis (the bacterium that causes TB), including dormant and drug-resistant forms, marking a significant step forward in TB drug research. By targeting a previously unexploited metabolic pathway essential for bacterial survival, JNJ-6640 may offer the potential to develop safer, shorter and more effective treatment regimens. Further optimisation and clinical evaluation are needed to assess its suitability for human use. The findings, published in Nature magazine recently, are the result of a collaborative effort between researchers at Johnson & Johnson and the London School of Hygiene & Tropical Medicine (LSHTM). JNJ-6640 works by inhibiting the enzyme PurF, which deprives the TB bacterium of essential metabolites, ultimately leading to bacterial death. Anil Koul, professor of translational discovery at LSHTM and lead corresponding author of the study, said, "Its ability to survive inside macrophages, resist antibiotics and adapt to hostile environments makes TB extremely difficult to eliminate," he said, noting that TB remains the leading infectious cause of death globally and infects nearly a quarter of the world's population. Unlike most current TB drugs which target actively replicating bacteria, JNJ-6640 remained effective under multiple stress-induced dormancy models, including nutrient deprivation, hypoxia (low-oxygen conditions) and intracellular infection. This is particularly relevant, as TB bacilli often persist in non-replicating states within granulomas (clusters of immune cells that wall off the infection), where they are shielded from antibiotics. "Many frontline TB drugs, such as isoniazid, lose efficacy in these dormant or low-oxygen conditions," said Koul. "JNJ-6640 retained activity in all these conditions suggesting that it could shorten the treatment, an essential goal in TB therapy," he added. Preclinical studies also indicate that JNJ-6640 may have potential in treating drug-resistant TB. "Replacing current drugs which carry significant toxicity risks is crucial. JNJ-6640's new mechanism and safety potential make it a strong candidate for future combination regimens," said Koul. In addition to its bactericidal activity, JNJ-6640 exhibited a post-antibiotic effect (continued killing of bacteria even after the drug is removed) in vitro. While this property could help reduce relapse rates and improve patient recovery, researchers are cautious in interpreting its long-term clinical relevance. One limitation of JNJ-6640 is its poor metabolic stability (it is broken down too quickly to be effective when given orally) in mice. To overcome this, the team developed a long-acting injectable (LAI) formulation. "The goal remains to develop an orally bioavailable molecule, but the LAI formulation allowed us to maintain therapeutic concentrations in vivo and validate the drug candidate's potential," said Koul. At present, JNJ-6640 is considered a validated lead drug candidate but not yet suitable for clinical trials. This discovery exemplifies the importance of academic-industry collaboration in addressing medical needs, said Koul. "Targeting novel bacterial pathways is not only feasible-it's essential. We need global funders and policymakers to prioritise TB drug development if we are to control, and eventually eliminate, this disease," he said....