New drug candidate targeting bacterial metabolism could cut TB treatment time
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, pointed out that the over-70,000-year-old human pathogen had evolved into a highly persistent organism. '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 showed bactericidal activity against both replicating and dormant TB populations. It 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. This broad-spectrum activity suggests that the drug candidate could contribute to treatment shortening, an essential goal in TB therapy.'
Preclinical studies also indicate that JNJ-6640 may have potential in treating drug-resistant TB. It demonstrated no cross-resistance with existing drugs and was effective in combination with bedaquiline and pretomanid—two key components of newer regimens for multidrug-resistant TB. 'Replacing current drugs like linezolid, which carries significant toxicity risks, or moxifloxacin, which is increasingly compromised by resistance, 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. 'We need more data to determine whether this effect will translate into reduced relapse or allow intermittent dosing in patients,' he said.
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. LAIs could also be useful for prophylactic therapy in high-risk individuals or those with poor adherence,' said Koul. At present, JNJ-6640 is considered a validated lead drug candidate but not yet suitable for clinical trials.
Koul emphasised that the discovery of JNJ-6640 exemplifies the importance of academic-industry collaboration in addressing unmet medical needs. 'This project brought together experts in microbiology, structural biology, chemistry and pharmacology,' he said. 'Targeting novel bacterial pathways is not only feasible—it's essential. We urgently need global funders and policymakers to prioritise TB drug development if we are to control, and eventually eliminate, this disease.'
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