Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion.

Mark Schiebler ; Karen Brown ; Krisztina Hegyi ; Sandra M Newton ; Maurizio Renna ; Lucy Hepburn ; Catherine Klapholz ; Sarah Coulter ; Andres Obregón-Henao ; Marcela Henao Tamayo ; +12 more... Randall Basaraba ; Beate Kampmann ORCID logo ; Katherine M Henry ; Joseph Burgon ; Stephen A Renshaw ; Angeleen Fleming ; Robert R Kay ; Karen E Anderson ; Phillip T Hawkins ; Diane J Ordway ; David C Rubinsztein ; Rodrigo Andres Floto ; (2015) Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. EMBO MOLECULAR MEDICINE, 7 (2). pp. 127-139. ISSN 1757-4676 DOI: 10.15252/emmm.201404137
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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 multidrug-resistant MTB strain, carbamazepine treatment reduced bacterial burden, improved lung pathology and stimulated adaptive immunity. We show that carbamazepine induces antimicrobial autophagy through a novel, evolutionarily conserved, mTOR-independent pathway controlled by cellular depletion of myo-inositol. While strain-specific differences in susceptibility to in vivo carbamazepine treatment may exist, autophagy enhancement by repurposed drugs provides an easily implementable potential therapy for the treatment of multidrug-resistant mycobacterial infection.


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