TB – the search for a cure

The current first-line treatment regimen for drug-sensitive TB (DS-TB) was established more than 40 years ago and many drug-resistant strains of the disease have emerged – an estimated 390,000 people were diagnosed with drug-resistant TB (DR-TB) in 2024. As resistance continues to emerge, new drugs are needed, including ones that attack the bacteria with novel methods, but new combinations of drugs are needed as well. And these new technologies need to work much more quickly, so that treatment does not last half a year or longer.

TB is also difficult to address because it is often strongly associated with poverty. Transmission is facilitated in settings with poor ventilation and close contact, such as underground mines, crowded workplaces and densely populated urban communities.  Undernutrition – commonly linked to poverty – weakens immune defences and increases the risk of developing TB disease after infection. The illness can also place a heavy financial burden on households when the primary wage earner becomes ill, further compounding economic hardship and vulnerability.

Combining all of these factors, it becomes difficult to develop a new antibiotic and bring it over the finish line. For private sector pharmaceutical companies, it may be difficult to justify the investment in TB drug development from a commercial perspective. From a humanitarian perspective, however, the rationale is clear.

Recognising these challenges, two important cross-sector collaborations were developed. The first, the TB Drug Accelerator (TBDA), brings together private, government and philanthropic experts on behalf of their employers. We work together to accelerate the development of new chemical entities, sharing compound libraries as well as early discovery insights. We also brainstorm and determine new targets on the bacterium for these compounds to attack, or new phenotypic approaches to combatting the infection; look for prospective chemical entities within the libraries of all participants and then collectively consider whether those compounds should be formally evaluated.

This key innovation – pre-competitive collaboration, where companies share early discovery insights to accelerate progress – has been difficult to find in more traditional drug development efforts. We’re bringing competitors and experts from different perspectives together to solve one of the most difficult challenges in modern medicine.

PAN-TB is a complement to TBDA, bringing together private, government and philanthropic experts to focus on regimen design, clinical trial coordination and parallel evaluation of combinations. This collaboration looks at potential compounds and determines which combinations should be evaluated as potential new TB treatment regimens.

How this all comes together can be seen with TB drug candidate TBD09. Merck (known as MSD outside the US and Canada) and the National Institutes of Health (NIH) worked together on the discovery of this compound through TBDA. Together they determined that the Gates Medical Research Institute (MRI) was the best partner to take TBD09 forward into clinical development.

TBD09 is an oxazolidinone, a class of antibiotic that already has one compound approved for DR-TB treatment. That medicine, linezolid, has a method of action that works well against most drug-resistant strains of TB but is difficult for patients to tolerate for extended treatment periods.

Linezolid’s side effects therefore make it impractical to be used for DS-TB, which still can be treated with medicines that are easier to tolerate, but the anti-TB potential of oxazolidinones motivates us to look at other compounds in that class of drugs. The major safety challenge for this class is related to mitochondrial toxicity. With linezolid, this translates into a requirement for routine laboratory monitoring while on treatment, which is infeasible for many areas with a high burden of TB. Yet the effectiveness of linezolid against TB has been, up until now, difficult to replicate.

Toxicity is very often a central challenge in developing antibiotics, even since the very first antibiotic, streptomycin, was discovered for TB by Albert Schatz, a graduate student working under microbiologist Selman Waksman in 1943.

Researchers have long sought antibiotics that are effective at killing TB but do not also cause harm to the patient over the long treatment period required to cure the disease.

Through TBDA, the Gates MRI has worked with Merck and NIH to develop TBD09 and bring it through preclinical evaluations and phase 1 clinical trials, revealing a safety profile and potential efficacy meriting further consideration. The compound is now being evaluated in a dose-ranging trial, with more advanced clinical trials to be coordinated through PAN-TB; all of this planned research will evaluate the compound’s potential in significantly reducing treatment time for both DS-TB and DR-TB.

A major challenge for drug development will be to improve upon the safety profile of the current standard-of-care first-line regimen. With drug-resistant TB continuing to be a major health threat, there is an ever-growing need to develop a new regimen that is ‘safer, simpler, shorter’. This cannot be accomplished without the cross-sector collaborations in TBDA and PAN-TB – TBD09 would probably not have advanced in the clinical trial process without cross-sector collaboration and each clinical trial further improves our knowledge of how the TB bacterium can be eradicated.

If the new compounds and regimens clear the clinical trial process, the next opportunity for cross-sector collaboration will come with the market rollout. New technologies will quickly lose their value if they remain on the shelf, inaccessible to the patients who need them but cannot afford or access them. Developing and ensuring access to global health products is a complex task, requiring strong collaborations with international, regional and country partners – including private-sector manufacturers and national healthcare systems – to be successful.

DS- and DR-TB kill more people than any other infectious disease – an estimated 1.23 million people combined in 2024. This is a disease that has not been solved by isolating experts in their organisations and sectors. Instead, we need to break out of the siloed approach and work together, collaboratively, to reinvent and improve TB treatment so that we can end this disease once and for all.

World Tuberculosis (TB) Day, observed annually on 24 March. raises awareness about the devastating health and economic consequences of TB, the world’s deadliest infectious disease. The 2026 theme, ‘Yes! We Can End TB: Led by countries, powered by people’, calls for urgent investment and action to reach global elimination goals.