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EMBO Mol Med. 2015 Feb;7(2):127-39. doi: 10.15252/emmm.201404137.

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

Author information

1
Department of Medicine, Cambridge Institute for Medical Research University of Cambridge, Cambridge, UK.
2
Department of Medicine, Cambridge Institute for Medical Research University of Cambridge, Cambridge, UK Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK.
3
Department of Paediatric Infectious Diseases and Allergy, Imperial College London, London, UK.
4
Department of Medical Genetics, Cambridge Institute for Medical Research University of Cambridge, Cambridge, UK.
5
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
6
Department of Infection and Immunity, University of Sheffield Western Bank, Sheffield, UK.
7
MRC Laboratory of Molecular Biology, Cambridge, UK.
8
The Inositide Laboratory, Babraham Institute Babraham Research Campus, Cambridge, UK.
9
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA arf27@cam.ac.uk dcr1000@cam.ac.uk D.Ordway@colostate.edu.
10
Department of Medical Genetics, Cambridge Institute for Medical Research University of Cambridge, Cambridge, UK arf27@cam.ac.uk dcr1000@cam.ac.uk D.Ordway@colostate.edu.
11
Department of Medicine, Cambridge Institute for Medical Research University of Cambridge, Cambridge, UK Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK arf27@cam.ac.uk dcr1000@cam.ac.uk D.Ordway@colostate.edu.

Abstract

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.

KEYWORDS:

autophagy; multidrug‐resistant; myo‐inositol; tuberculosis

PMID:
25535254
PMCID:
PMC4328644
DOI:
10.15252/emmm.201404137
[Indexed for MEDLINE]
Free PMC Article

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