New Drug Target Found for Fighting Drug-Resistant Tuberculosis | Medical Xpress

The fight against tuberculosis (TB) has received a significant boost with the discovery of a potential new drug target. Researchers from Imperial College London and the London School of Hygiene & Tropical Medicine (LSHTM) have identified an enzyme, PurF, within the Mycobacterium tuberculosis bacteria that, when inhibited, prevents the bacteria from replicating. This finding, published in Nature, offers a promising avenue for developing new treatments to combat drug-resistant strains of TB, a disease that remains one of the world’s leading causes of death.

TB continues to be a major global health challenge, responsible for over 1.25 million deaths in 2023. Dr. Gerald Larrouy-Maumus, from Imperial’s Department of Life Sciences, emphasizes the scale of the problem, stating that TB is “still a major global problem” and “an under-recognized problem even in the U.K.” The difficulty in treating TB stems from the bacteria’s resilience to antibiotics, requiring lengthy and complex treatment regimens that patients often struggle to complete, fostering the development of drug resistance.

The Challenge of Drug Resistance

The evolution of drug-resistant TB strains is a critical concern. Prolonged antibiotic courses, while necessary to eradicate the infection, create selective pressure, allowing resistant bacteria to thrive and spread. This necessitates a continuous search for novel drug targets and therapies. The research team, collaborating with Janssen Pharmaceutica (now Johnson & Johnson Innovative Medicine), focused on identifying vulnerabilities within the bacteria that could be exploited by new drugs.

Their investigation led to the identification of PurF, an enzyme crucial for the synthesis of purines – essential molecules for bacterial metabolism and signaling. The team discovered that inhibiting PurF effectively halts bacterial replication. This is particularly significant because, unlike some bacteria that can scavenge purines from their host, M. Tuberculosis appears unable to acquire sufficient purines from human or animal tissues to survive when PurF is blocked. This makes PurF a particularly attractive target for drug development.

How the Discovery Was Made

The researchers screened thousands of chemical compounds to identify those with potent anti-TB activity. One molecule, JNJ-6640, stood out for its effectiveness in killing M. Tuberculosis. Dr. William Pearson at LSHTM described the finding as “incredibly potent against TB.” Further analysis, utilizing genetic analysis, protein studies, and microscopy, revealed the mechanism of action: JNJ-6640 inhibits the PurF enzyme.

To validate their findings, the team conducted in vivo trials using animal models. These experiments demonstrated that JNJ-6640 effectively reduced TB infection in mice. While JNJ-6640 itself isn’t suitable for use as a drug due to stability issues, the discovery that PurF inhibition is an effective strategy opens up new possibilities for developing alternative drug candidates.

Understanding the Role of PurF in M. Tuberculosis

Purines are fundamental building blocks for DNA and RNA, essential for all living cells. M. Tuberculosis requires a constant supply of purines to grow and replicate. The PurF enzyme plays a vital role in the de novo purine biosynthesis pathway – the process by which the bacteria creates its own purines. By blocking PurF, researchers effectively starve the bacteria of these essential components, halting its growth.

The LSHTM maintains a dedicated TB Modelling Group, which uses mathematical models to understand the epidemiology of tuberculosis and inform policy decisions. This type of modeling is crucial for predicting the impact of new treatments and strategies.

Beyond JNJ-6640: The Future of TB Drug Development

The identification of PurF as a viable drug target represents a significant step forward in the fight against TB. Researchers can now focus on developing new compounds that specifically inhibit PurF, potentially overcoming existing drug resistance mechanisms. The team’s work builds on growing understanding of the complex phenotypic variation within M. Tuberculosis populations, as highlighted in recent research analyzing single-cell behavior under stress (bioRxiv preprint). This understanding is crucial for developing treatments that can effectively target diverse bacterial subpopulations.

The discovery also underscores the importance of collaborative research efforts. The partnership between Imperial College London, LSHTM, and Johnson & Johnson Innovative Medicine demonstrates the power of combining academic expertise with pharmaceutical industry resources to accelerate drug discovery.

What’s Next for TB Research?

The next steps involve further research to identify and develop stable, effective PurF inhibitors that can be tested in clinical trials. Researchers will also need to investigate potential off-target effects and ensure the safety and efficacy of these new compounds. The World Health Organization (WHO) continuously monitors new developments in TB treatment and updates its guidelines accordingly. Ongoing surveillance and research are essential to track the emergence of drug resistance and adapt treatment strategies.

This discovery offers a renewed sense of hope in the ongoing battle against tuberculosis, a disease that continues to disproportionately affect vulnerable populations worldwide. The focus now shifts to translating this promising research into tangible benefits for patients in need.