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

Autor: Lucy Hepburn, Randall J. Basaraba, Stephen A. Renshaw, R.A. Floto, Beate Kampmann, Catherine Klapholz, Sandra M. Newton, Karen E. Anderson, Angeleen Fleming, Krisztina Hegyi, Robert R. Kay, Joseph Burgon, Karen Brown, Sarah Coulter, David C. Rubinsztein, Mark Schiebler, Maurizio Renna, Diane J. Ordway, Andrés Obregón-Henao, Katherine M. Henry, Phillip T. Hawkins, Marcela Henao Tamayo
Přispěvatelé: Fleming, Angeleen [0000-0003-3721-7126], Anderson, Karen E [0000-0002-7394-6660], Hawkins, Phillip Thomas [0000-0002-6979-0464], Rubinsztein, David [0000-0001-5002-5263], Floto, Andres [0000-0002-2188-5659], Apollo - University of Cambridge Repository, Schiebler, Mark, Brown, Karen, Hegyi, Krisztina, Newton, Sandra M., Renna, Maurizio, Hepburn, Lucy, Klapholz, Catherine, Coulter, Sarah, Obregón-Henao, Andre, Henao Tamayo, Marcela, Basaraba, Randall, Kampmann, Beate, Henry, Katherine M., Burgon, Joseph, Renshaw, Stephen A., Fleming, Angeleen, Kay, Robert R., Anderson, Karen E., Hawkins, Phillip T., Ordway, Diane J., Rubinsztein, David C., Floto, Rodrigo Andres
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Macrophage
Antitubercular Agents
Drug Evaluation
Preclinical
Mycobacterium tuberculosi
Research & Experimental Medicine
Pharmacology
PATHWAY
Antitubercular Agent
Mice
INFECTION
Anticonvulsant
Multidrug-resistant
Research Articles
Zebrafish
HYPOTHESIS
TOR Serine-Threonine Kinase
biology
TOR Serine-Threonine Kinases
11 Medical And Health Sciences
Acquired immune system
CHEMOTAXIS
3. Good health
Carbamazepine
Medicine
Research & Experimental
tuberculosis
DICTYOSTELIUM
Molecular Medicine
Anticonvulsants
Female
Life Sciences & Biomedicine
Dautophagy
Intracellular
Human
autophagy
myo‐inositol
DEFENSE
Tuberculosi
IMMUNITY
Cell Line
Mycobacterium tuberculosis
In vivo
Immunity
LITHIUM
Animals
Humans
PI3K/AKT/mTOR pathway
Science & Technology
Animal
multidrug‐resistant
Macrophages
Autophagy
06 Biological Sciences
biology.organism_classification
Mice
Inbred C57BL
Multiple drug resistance
Disease Models
Animal
Myo-inositol
Inositol
Zdroj: ResearcherID
EMBO Molecular Medicine
ISSN: 1757-4676
Popis: 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.
Databáze: OpenAIRE
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