dictyNews Volume 40 Number 30

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dictyNews 
Electronic Edition 
Volume 40, number 30 
December 05, 2014 

Please submit abstracts of your papers as soon as they have been 
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http://dictybase.org/db/cgi-bin/dictyBase/abstract_submit. 

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========= 
Abstracts 
========= 

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 Obreg—n-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 [rrk@mrc-lmb.cam.ac.uk]    
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[End dictyNews, volume 40, number 30]