Tuberculosis (TB) is an ancient infectious disease caused by bacteria, and it is by far the greatest infectious killer of humanity.
In 2024, an estimated 10.7 million people fell ill with TB worldwide, including a total of 1.23 million deaths. Despite the availability of antibiotics, TB continues to pose a major global health challenge.
Drug tolerance and drug resistance are major impediments to treatment of TB and therefore the eradication of TB.
Effective cure requires long treatment with multiple antibiotics, a regimen that is difficult to sustain particularly in low-income settings. This is due to the bacteria becoming drug tolerant, i.e., temporarily resistant to antibiotics. When treatment is interrupted, these bacteria can rebound.
Our work overturned the long-standing idea that tolerance is due to the bacteria ‘going to sleep’. Instead, we showed that when the TB bacterium Mycobacterium tuberculosis enters host immune cells, actively growing bacteria switch on efflux pumps that expel antibiotics from the cell. This explains why prolonged, multi-drug treatment is required and why standard therapies can fail.
We then identified some existing, low-cost medicines – including verapamil, which is widely used for heart conditions, and proton pump inhibitors, commonly prescribed for acid reflux and stomach ulcers – that can reduce or reverse TB drug tolerance.
One of these approaches has already completed a Phase I clinical trial, showing safety and effective blood levels in people to treat drug tolerance.
We have also shown that drug efflux can also drive genetic drug resistance, including resistance to bedaquiline, a cornerstone drug for multi drug resistant TB but is already facing resistance rates of up to 20–25% in some regions.
Combining structural biology and molecular genetics, we revealed the structure of the efflux pump MmpS5L5, which expels bedaquiline and multiple other existing and pipeline TB drugs. We’re trying to understand how drug transport happens and how it might be overcome.
At the population level, we have also challenged the widespread belief that a quarter to a third of the world’s population harbours latent TB. By analysing more than 200 years of epidemiological and clinical data, we showed that most people infected with TB either develop disease within months or clear the bacteria altogether, retaining immunological memory that shows in TB blood tests. This has led to WHO’s corrigendum and revised guidelines on latent TB.
Over the decades, we've been studying the disease and at the same time helping to develop more and more genetic tools in the field.
We have developed the zebrafish model to study TB infection in living organisms. Through the mix and match of host and bacterial mutations with live imaging, we are able to understand how TB bacteria cause the disease, and what genetic mutations could make us more susceptible.
Here at Cambridge and housed in the MRC Laboratory of Molecular Biology, it’s a very nice and supportive atmosphere paired with excellent facilities. While I’ve maintained my collaborations with people in Washington, I’ve built new ones here with structural biologists, biochemists, and others across disciplines.
References
- WHO. Tuberculosis fact sheet. 2025. https://www.who.int/news-room/fact-sheets/detail/tuberculosis
- Adams KN, Takaki K, Connolly LE, et al. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell. 2011;145(1):39-53. doi:10.1016/j.cell.2011.02.022
- Adams KN, Szumowski JD, Ramakrishnan L. Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple anti-tubercular drugs. J Infect Dis. 2014;210(3):456-466. doi:10.1093/infdis/jiu095
- Lake MA, Adams KN, Nie F, et al. The human proton pump inhibitors inhibit Mycobacterium tuberculosis rifampicin efflux and macrophage-induced rifampicin tolerance. Proc Natl Acad Sci U S A. 2023;120(7):e2215512120. doi:10.1073/pnas.2215512120
- Fountain AJ, Böhning J, McLaughlin SH, et al. Structural and functional analysis of the Mycobacterium tuberculosis MmpS5L5 efflux pump presages a pathway to increased bedaquiline resistance. Preprint. bioRxiv. 2025;2025.06.24.661325. Published 2025 Jun 24. doi:10.1101/2025.06.24.661325
- Behr MA, Kaufmann E, Duffin J, Edelstein PH, Ramakrishnan L. Latent Tuberculosis: Two Centuries of Confusion. Am J Respir Crit Care Med. 2021;204(2):142-148. doi:10.1164/rccm.202011-4239PP
Credits:
Image credit: MRC Laboratory of Molecular Biology, CDC on Unsplash, JK Shanahan, and Antonio Pagan