Proton Gradient and antibiotic persistence in Mycobacterium tuberculosis
Tuberculosis (TB) remains a global health emergency, with persistent drug-tolerant cells posing a major threat to treatment success. These persisters, a subpopulation of Mycobacterium tuberculosis, are highly refractory to antibiotics, contributing to infection relapse, chronic disease, and treatment failure. However, studying these elusive cells has been challenging due to their transient nature and extremely low frequency. To overcome this, we developed a novel chemical approach to induce a drug-tolerant state across an entire bacterial population. Our model revealed that chemically-induced persister cells suppress their electron transport chain activities and energy metabolism while maintaining an enhanced oxidative stress response, an adaptive strategy that likely sustains their survival. Notably, our findings suggest a direct link between intracellular acidification and TB persistence. Furthermore, we identified key genes essential for TB persistence, which could serve as novel drug targets or persistence biomarkers to improve TB treatment strategies. These findings offer a novel approach to study persistent TB cells and could pave the way for more effective therapies against this deadly pathogen.