The growing challenge of drug resistance

TB is one of the most persistent infectious diseases, affecting over 10 million people each year and causing an estimated 1.25 million deaths. While major advances in diagnostics and treatment have saved millions of lives, the fight against TB is far from over. A growing concern is drug-resistant TB, particularly multidrug-resistant TB (MDR-TB), which threatens global progress and makes effective treatment increasingly challenging. Traditionally, treatment for MDR-TB has been long, costly and often associated with severe side effects. In 2022, the World Health Organization (WHO) recommended the BPaL(M) regimen, a shorter six-month treatment, based on evidence from clinical trials, including TB-PRACTECAL. The findings suggest that BPaL(M) offers a more effective and patient-friendly alternative, improving treatment outcomes and reducing the burden on both patients and healthcare systems.

"Drug-resistant TB is not just developing spontaneously – it is actively being transmitted from patient to patient."

However, latest research from Swiss TPH has revealed that resistance to these new drugs is already emerging. TB bacteria have a long history of adapting to treatment, and the latest findings confirm that this challenge persists. A Swiss TPH-led study, published in the New England Journal of Medicine, analysed the genomes of nearly 90,000 TB strains from around the world. The results showed that resistance to the newly recommended treatment regimen is not only developing – but also spreading between patients.

“This is alarming because drug-resistant TB is not just developing spontaneously – it is actively being transmitted from patient to patient,” explains Sébastien Gagneux, Head of the Medical Parasitology and Infection Biology Department at Swiss TPH and senior author of the study. “We already knew that resistance could occur, but seeing it spread so quickly after the introduction of new drugs highlights the urgent need for action.”

A new research project to stay ahead of resistance

To better understand how extensively drug-resistant TB evolves, Swiss TPH researchers, in collaboration with the Institute of Tropical Medicine in Antwerp (Belgium) and the National Centre for Tuberculosis and Lung Diseases in Tbilisi (Georgia), have launched a new project, funded by the Swiss National Science Foundation (SNSF). The study aims to investigate how historical adaptations of Mycobacterium tuberculosis influence the development of resistance to the newly recommended BPaL(M) treatment regimen.

Recent findings indicate that MDR-TB in Georgia is driven by a few highly transmissible strains, many of which are resistant to multiple first- and second-line drugs. Second-line drugs are drugs that are given when initial treatment (first-line drugs) does not work, or no longer works. Additionally, previous research has shown that 30% of MDR-TB cases in the country were linked to incarceration, suggesting that prisons have played a significant role in the emergence and spread of drug-resistant TB. The project will examine how past TB outbreaks, particularly in prison settings, have contributed to the evolution of these strains and their drug resistance patterns.

The researchers will analyse over 30,000 Mycobacterium tuberculosis samples collected in Georgia over the past three decades, linking genomic data with clinical and epidemiological information. “By studying past adaptation to older TB treatments, we hope to understand the mechanisms of these strains to develop resistance to the new treatment regimens,” explains Gagneux.

To achieve this, the study will follow a multi-step approach by combining long-read genome sequencing, RNA sequencing, proteomics, and quantitative drug susceptibility testing with data from an ongoing MDR-TB patient cohort in Georgia that has been monitored since 2021.

“By integrating genetic, clinical, and epidemiological data, we aim to uncover how past adaptations shape drug resistance today,” said Gagneux. “This knowledge is key to improving TB diagnostics, surveillance, and treatment strategies, ultimately helping to prevent further resistance and ensuring that new therapies remain effective for as long as possible.”

“TB control must evolve with the pathogen. Research is our most powerful tool in this fight.”

The impact of this research extends beyond Georgia, as MDR-TB is a global challenge, with cases reported in nearly every region of the world. Its findings could help inform global TB control strategies and may contribute to the development of treatment guidelines and public health policies by the WHO and other global health bodies.

A call to action for World TB Day

On this World TB Day, we reaffirm our commitment to fighting TB and MDR-TB through innovative research and global collaboration. While progress has been made, drug-resistant TB remains a challenge that can only be tackled through sustained and consorted efforts.   

Swiss TPH contributes to this fight through research ranging from basic science to clinical trials and health systems strengthening. Working with partners such as the Ifakara Health Institute (IHI) in Tanzania and the National Center for Tuberculosis and Lung Diseases in Georgia, we study antibiotic resistance, host-pathogen interactions, and immune responses, while also evaluating TB programmes and testing new diagnostics, drugs, and vaccines.

As Gagneux emphasises: “TB control must evolve with the pathogen. Research is our most powerful tool in this fight.” Understanding drug resistance is key to ensuring the long-term effectiveness of new treatments like BPaL(M). This World TB Day is a reminder that political commitment for sustained investment, policy action, and innovation are essential to overcome TB as a public health threat.