Functional drug screening reveals anticonvulsants as enhancers of mTOR‐independent autophagic killing of Mycobacterium tuberculosis through inositol depletion
Author(s)
Type
Journal Article
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.
Date Issued
2014-12-22
Date Acceptance
2014-12-22
Citation
EMBO Molecular Medicine, 2014, 7 (2), pp.127-139
ISSN
1757-4676
Publisher
EMBO
Start Page
127
End Page
139
Journal / Book Title
EMBO Molecular Medicine
Volume
7
Issue
2
Copyright Statement
© 2014 The Authors. Published under the terms of the CC BY 4.0 license
License URL
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
Dautophagy
multidrug-resistant
myo-inositol
tuberculosis
INFECTION
LITHIUM
CHEMOTAXIS
DICTYOSTELIUM
MACROPHAGES
HYPOTHESIS
ZEBRAFISH
IMMUNITY
DEFENSE
PATHWAY
autophagy
multidrug‐resistant
myo‐inositol
Animals
Anticonvulsants
Antitubercular Agents
Autophagy
Carbamazepine
Cell Line
Disease Models, Animal
Drug Evaluation, Preclinical
Female
Humans
Inositol
Macrophages
Mice
Mice, Inbred C57BL
Mycobacterium tuberculosis
TOR Serine-Threonine Kinases
Tuberculosis
Zebrafish
06 Biological Sciences
11 Medical And Health Sciences
Publication Status
Published