dictyNews Electronic Edition Volume 40, number 30 December 05, 2014 Please submit abstracts of your papers as soon as they have been accepted for publication by sending them to dicty@northwestern.edu or by using the form at http://dictybase.org/db/cgi-bin/dictyBase/abstract_submit. Back issues of dictyNews, the Dicty Reference database and other useful information is available at dictyBase - http://dictybase.org. Follow dictyBase on twitter: http://twitter.com/dictybase ========= 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] ============================================================== [End dictyNews, volume 40, number 30]