Open AccessFunctional drug screening reveals anticonvulsants as enhancers of mTOR‐independent autophagic killing of Mycobacterium tuberculosis through inositol depletion
Author(s) -
Schiebler Mark,
Brown Karen,
Hegyi Krisztina,
Newton Sandra M,
Renna Maurizio,
Hepburn Lucy,
Klapholz Catherine,
Coulter Sarah,
ObregónHenao Andres,
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
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404137
Subject(s) - autophagy , mycobacterium tuberculosis , pi3k/akt/mtor pathway , carbamazepine , biology , multiple drug resistance , microbiology and biotechnology , drug resistance , tuberculosis , in vivo , intracellular parasite , pharmacology , immunology , medicine , immune system , apoptosis , signal transduction , biochemistry , pathology , neuroscience , epilepsy
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.