dictyNews
Electronic Edition
Volume 40, number 30
December 05, 2014
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Abstracts
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Functional drug screening reveals anticonvulsants as enhancers of
mTOR-independent autophagic killing of Mycobacterium tuberculosis
through inositol depletion.
Mark Schiebler1,9, Karen Brown1,2,9, Krisztina Hegyi1,9†, Sandra M.
Newton3,9, Maurizio Renna4,9, Lucy Hepburn1, Catherine Schaffner1,
Sarah Coulter1, Andres Obregón-Henao5, Marcela Henao Tamayo5,
Randall Basaraba5, Beate Kampmann3, Katherine M. Henry6, Joseph
Burgon6, Stephen A. Renshaw6, Angeleen Fleming4, Robert R. Kay7,
Karen E. Anderson8, Phillip T. Hawkins8, Diane J. Ordway5, David C.
Rubinsztein4 & R. Andres Floto1,2.
1Departments of Medicine and 4Medical Genetics, Cambridge Institute
for Medical Research, University of Cambridge, UK.
2Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge,
UK
3Department of Paediatric Infectious Diseases and Allergy, Imperial
College London, 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
EMBO Molecular Medicine, in press
Mycobacterium tuberculosis (MTB) remains a major challenge to global
health made worse by the spread of multi-drug 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 man. 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
multi-drug resistant MTB strain, carbamazepine treatment reduced
bacterial burden, improved lung pathology and stimulated adaptive
immunity. We show that carbamazepine induces anti-microbial autophagy
through a novel, evolutionarily conserved, mTOR-independent pathway
controlled by cellular depletion of myoinositol. 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.
Submitted by Rob Kay [[log in to unmask]]
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