Mycobacterium tuberculosis overcomes phosphate starvation by extensively remodelling its lipidome with phosphorus-free lipids

Tuberculosis (TB) is the biggest cause of death from infectious disease worldwide. The causative agent, Mycobacterium tuberculosis (Mtb), possesses a complex cell envelope comprised of multiple classes of unique lipids. The macrophage phagosome is a key reservoir of infection in pulmonary TB and multiple studies have shown that inorganic phosphate (Pi) is limiting in this environment. Here, we show that during Pi restriction the Mtb lipidome markedly remodels such that phospholipids are replaced with multiple classes of phosphorus-free lipids. This envelope lipidome remodelling suggests that standard Mtb culture conditions that use media with high concentrations of Pi do not reflect the physiologic environment during infection, thereby undermining vaccine and drug development for tuberculosis. Further, we discover that Mtb can metabolise phospholipid polar heads abundant in host pulmonary surfactant as an alternative phosphate source. Therefore, we present two mechanisms where Mtb manipulates lipid metabolism to overcome host restriction.