Tuberculosis bacteria develop drug tolerance inside patients, study shows

Tuberculosis remains a major global health challenge, in part because some patients do not respond to therapy as expected. Researchers led by Sònia Borrell set out to learn whether a phenomenon called antibiotic tolerance might help explain these poor responses. Tolerance is different from outright drug resistance: tolerant bacteria survive antibiotic exposure for longer without carrying the classic resistance changes that render drugs ineffective. The team focused on two troubling clinical scenarios. The first involved people with drug-susceptible TB who nevertheless remained culture positive for long periods — in one group up to six years — a situation the authors call recalcitrant TB. The second involved people with multidrug-resistant TB (MDR-TB) in whom resistance increased during treatment. By following these patients over time and collecting serial Mycobacterium tuberculosis (Mtb) samples from each person, the researchers could watch what happened to the bacteria inside each patient during treatment. Their central question was whether evolving drug tolerance could explain delayed culture conversion in recalcitrant TB or lead to resistance amplification during MDR-TB therapy.

To answer this question, the investigators measured how well Mtb isolates survived antibiotic exposure over time. They tested tolerance to rifampicin (RIF) in strains from the drug-susceptible, recalcitrant TB patients and tolerance to moxifloxacin (MFX) in strains from the MDR-TB patients. The team used a real-time time-kill assay to quantify survival under drug exposure, allowing them to detect changes in tolerance as infections progressed. The results showed that rifampicin tolerance did evolve within patients: RIF tolerance increased over time by up to roughly 1.5-fold in some cases. Despite this measurable increase, there was no clear evidence that higher RIF tolerance explained delayed culture conversion in the recalcitrant TB group. In the MDR-TB group, tolerance to MFX behaved differently: MFX tolerance tended to decrease over time and was, in these data, negatively associated with resistance amplification rather than promoting it. Overall, the experiments confirmed that antibiotic tolerance can change within individual patients during treatment.

Taken together, these observations offer a nuanced picture. The work confirms that antibiotic tolerance is a dynamic trait that evolves in Mycobacterium tuberculosis inside people during therapy, but it also shows that detectable increases in tolerance did not translate into the expected clinical outcomes in this study. Specifically, rising rifampicin tolerance did not appear to drive the prolonged culture positivity seen in recalcitrant TB patients, and declining moxifloxacin tolerance in MDR-TB patients did not herald resistance growth; instead, MFX tolerance was negatively associated with resistance amplification. The authors conclude that tolerance alone is unlikely to be the sole explanation for poor treatment responses and that other factors — host, bacterial, or treatment related — must be investigated. These results point researchers toward a broader search for the causes of recalcitrant TB and resistance amplification and suggest that monitoring tolerance by itself may not be sufficient to predict or prevent adverse outcomes during TB treatment.