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Background  Autophagy has been shown recently to play an important role in the intracellular survival of several pathogenic bacteria. In this study, we investigated the effect of a novel small-molecule autophagy-inducing agent, AR-12, on the survival of  Francisella tularensis , the causative bacterium of tularemia in humans and a potential bioterrorism agent, in macrophages.    Methods and results  Our results show that AR-12 induces autophagy in THP-1 macrophages, as indicated by increased autophagosome formation, and potently inhibits the intracellular survival of  F. tularensis  (type A strain, Schu S4) and  F. novicida  in macrophages in association with increased bacterial co-localization with autophagosomes. The effect of AR-12 on intracellular  F. novicida  was fully reversed in the presence of the autophagy inhibitor, 3-methyl adenine or the lysosome inhibitor, chloroquine. Intracellular  F. novicida  were not susceptible to the inhibitory activity of AR-12 added at 12 h post-infection in THP-1 macrophages, and this lack of susceptibility was independent of the intracellular location of bacteria.    Conclusion  Together, AR-12 represents a proof-of-principle that intracellular  F. tularensis  can be eradicated by small-molecule agents that target innate immunity.

Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent