Table 2.
Potential Tuberculosis Therapies Based on Autophagy Manipulation
| Therapy | Effects | Reference |
|---|---|---|
| Sirolimus (rapamycin), everolimus | mTORC1 inhibitors and autophagy inducers; increase BCG vaccine efficacy | Gutierrez et al. (2004), Jagannath et al. (2009), Gupta et al. (2014) |
| SMERs | Synergistic effect with rapamycin on autophagy, acting independently or downstream of mTOR; autophagy inducer | Floto et al. (2007) |
| Nitazoxanide (tizoxanide) | Inhibitor of mTORC1 signaling and autophagy inducer; kills mycobacteria directly by an unknown mechanism | de Carvalho et al. (2009), Lam et al. (2012) |
| IFN-γ | Increases production of reactive nitrogen species in macrophages and induces autophagy | Chan et al. (1992), MacMicking et al. (2003), Singh et al. (2006) |
| Lactic acid bacteria | Increase production of IFN-γ and decrease the autophagy negative regulators, IL-4 and IL-13; induce autophagy | Ghadimi et al. (2010) |
| Vitamin D | Required for IFN-γ-induced autophagy | Campbell and Spector (2012) |
| Lithium, carbamazepine, sodium valproate | Target the d-myo-inosiltol-1,4,5 triphosphate (IP3)-regulated pathway, deplete intracellular inositol, and induce autophagy in an mTOR-independent way | Sarkar et al. (2005) |
| Tamoxifen | Inducer of autophagy in a Beclin-1-dependent manner | Wienecke et al. (2006) |
| Ridaifen-B | Tamoxifen derivative that induces autophagy through an unknown Beclin-1-independent mechanism | Nagahara et al. (2013) |
| Gefitinib | Induces autophagy (although it is not clear, the authors postulate that gefitinib-induction of autophagy relies on p38 MAPK inhibition) | Stanley et al. (2014) |
| Nortriptyline | Induces autophagy by an unknown mechanism | Sundaramurthy et al. (2013) |
| Fluoxetine | Induces autophagy possibly due to enhanced TNF-α secretion | Stanley et al. (2014) |
| Statins | Promote autophagy by inhibiting the HMG-CoA reductase pathway and in an mTOR-dependent way; improve the efficacy of first-line TB drugs | Wei et al. (2013), Lobato et al. (2014), Parihar et al. (2014), Skerry et al. (2014) |
| Ag85-overexpressing strains for vaccines | Ag85 is targeted by the autophagy-lysosome pathway and increases antigen presentation | Horwitz et al. (2006), Jagannath et al. (2009) |
| DNA vaccines (Ag85, Hsp65, Esx genes) | Potentiate INF-γ production and induce autophagy | Meerak et al. (2013), Zarate-Blades et al. (2013), Villarreal et al. (2014) |
BCG, bacilli Calmette Guerin; IFN-γ, interferon-γ; mTOR, mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; SMERs, small-molecule enhancers of rapamycin; TNF, tumor necrosis factor.