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.
Highlights
The increase in infections with multidrug-resistant (MDR) and extensive drug-resistant (XDR) Mycobacterium tuberculosis (MTB), requiring longer and more toxic drug regimens which often fail, has created significant barriers to effective treatment of tuberculosis in both well-resourced and resource-poor settings (Nathanson et al, 2010; Lienhardt et al, 2012) and illustrates the pressing need for new, more effective therapies
We have previously shown that novel mTOR-independent pathways exist to activate autophagy (Sarkar et al, 2005; Williams et al, 2008)
Through high-throughput screening of a library of compounds enriched for drugs already FDA-approved for non-infectious indications, we identified several compounds able to activate mTOR-independent autophagic killing of intracellular mycobacteria
Summary
The increase in infections with multidrug-resistant (MDR) and extensive drug-resistant (XDR) Mycobacterium tuberculosis (MTB), requiring longer and more toxic drug regimens which often fail, has created significant barriers to effective treatment of tuberculosis in both well-resourced and resource-poor settings (Nathanson et al, 2010; Lienhardt et al, 2012) and illustrates the pressing need for new, more effective therapies. Some progress has been made in developing novel antibiotics Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK. MRC Laboratory of Molecular Biology, Cambridge, UK. The Inositide Laboratory, Babraham Institute, Babraham Research Campus, Cambridge, UK †.
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