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Significance Tuberculosis (TB) remains a global health concern despite the availability of antibiotics to treat this disease. Understanding the metabolic state of the bacteria during infection is crucial to identifying novel drug targets that are vital toMycobacterium tuberculosis survival. Here, we demonstrate thatM. tuberculosis central carbon metabolism is altered in response to acidic pH, a host-imposed stress, causing the pathogen to depend on lipids for growth. Continuous fatty acid supplementation at acidic pH is a simple and effective approach to investigateM. tuberculosis in a metabolic state that more closely reflects that of bacteria during infection and might facilitate the identification of anti-TB drugs with a greater likelihood to be active in vivo.

Growth ofMycobacterium tuberculosisat acidic pH depends on lipid assimilation and is accompanied by reduced GAPDH activity