Press release Ecofect - 24 June 2021

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the leading causes of death from infectious disease worldwide, with 10 million new cases and 1.4 million deaths in 2019. Mtb is able to persist inside the patient for months or years, requiring long courses of antibiotic treatment.
This study, developed by researchers from the International Center for Infectious Diseases (CIRI) and the Laboratory of Biometry and Evolutive Biology (LBBE) and financed by the Ecofect LabEx through the EVOFIT-COMBO-TB project, focused on TB patients with delayed response to treatment and performed a genetic characterisation of Mtb clinical isolates to look for subpopulations that might be tolerant to anti-TB drugs. We found that Mtb clinical isolates obtained from 9/15 patients with delayed response to treatment contained different subpopulations.
In addition, in vitro exposure to a leading anti-tuberculosis drug, rifampicin, revealed subpopulations of Mtb in 6/15 isolates, none of which were linked to known drug resistance mechanisms. In contrast, rifampicin exposure revealed Mtb subpopulations in only 2/20 isolates originating from the control cohort of patients who had a rapid response to treatment.
Furthermore, we characterised a variant of Mtb isolated from a subpopulation that was in the minority in the initial clinical isolate but became the majority after exposure to rifampicin in vitro. We found that this variant had a modified lipid envelope and was able to grow in the presence of RIF and within human macrophages, which are immune cells central to the control of Mtb infections. Finally, we developed a pharmacological modelling and found that this type of variant may be related to a poor response to treatment. In conclusion, the search for particular Mtb subpopulations or variants may help to detect patients at risk of treatment failure and provide additional guidance for the management of TB.