ZFIN ID: ZDB-PUB-141224-12
Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion
Schiebler, M., Brown, K., Hegyi, K., Newton, S.M., Renna, M., Hepburn, L., Klapholz, C., Coulter, S., Obregón-Henao, A., Henao Tamayo, M., Basaraba, R., Kampmann, B., Henry, K.M., Burgon, J., Renshaw, S.A., Fleming, A., Kay, R.R., Anderson, K.E., Hawkins, P.T., Ordway, D.J., Rubinsztein, D.C., Floto, R.A.
Date: 2015
Source: EMBO Molecular Medicine   7(2): 127-39 (Journal)
Registered Authors: Burgon, Joseph, Fleming, Angeleen, Henry, Katherine, Renshaw, Steve A.
Keywords: autophagy, multidrug‐resistant, myo‐inositol, tuberculosis
MeSH Terms:
  • Animals
  • Anticonvulsants/administration & dosage*
  • Antitubercular Agents/administration & dosage*
  • Autophagy/drug effects*
  • Carbamazepine/administration & dosage*
  • Cell Line
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Inositol/metabolism*
  • Macrophages/drug effects
  • Macrophages/immunology
  • Mice
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis/drug effects*
  • Mycobacterium tuberculosis/metabolism
  • TOR Serine-Threonine Kinases/genetics
  • TOR Serine-Threonine Kinases/metabolism
  • Tuberculosis/drug therapy*
  • Tuberculosis/immunology
  • Tuberculosis/metabolism
  • Tuberculosis/physiopathology*
  • Zebrafish
PubMed: 25535254 Full text @ EMBO Mol. Med.
FIGURES
ABSTRACT
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.
ADDITIONAL INFORMATION No data available