biostudies-literatureSchiebler MMedical Research CouncilWellcome TrustBiotechnology and Biological Sciences Research Council127-39https://www.ebi.ac.uk/biostudies/studies/S-EPMC4328644biostudies-literatureUnknown7(2)Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell-based screening of FDA-approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum, while in mice infected with a highly virulent multidrugEMBO molecular medicineFunctional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion.PMC4328644100140MC_U105115237MR/M004864/1095317G108/595G0701932BBS/E/B/000C0415Renna MBasaraba RRubinsztein DCHenao Tamayo MAnderson KEObregon-Henao AOrdway DJHawkins PTNewton SMRenshaw SACoulter SFleming AKay RRBrown KHenry KMKampmann BFloto RAHegyi KKlapholz CHepburn LSchiebler MBurgon JfalseFunctional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion.Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell-based screening of FDA-approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum, while in mice infected with a highly virulent multidrug2015-01-01T00:00:00Z2015 Feb2025-04-04T10:01:39.149Z2019-03-27T01:45:13ZS-EPMC43286442553525410.15252/emmm.201404137