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Antidepressant Amoxapine inhibits intracellular mycobacterial survival by inducing autophagy

Jia Wang1, Ashok K. Chopra1, and Sunhee Lee1*
1 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA

Host-directed antimicrobial drugs that enhance the intracellular killing of mycobacteria are highly desirable, since they could circumvent the development of antibiotic resistance strains. Because intracellular pathogens such as Yersinia pestis and Mycobacterium tuberculosis (Mtb) both infect macrophages and manipulate host machineries to favor their survival, we hypothesize that host-directed drugs against Yersinia pestis that targeting common host defense pathways may also be protective against Mtb. Therefore, we tested 58 FDA approved drugs that protect against Yersinia pestis induced host cell cytotoxicity against Mycobacterium bovis BCG induced cell death. After that, the effects of hit drugs on intracellular BCG survival was evaluated. Two antidepressants, Amoxapine, and Trimipramine maleate were identified to not only inhibit BCG induced murine macrophage cytotoxicity, but also enhance intracellular killing of BCG and Mtb strain H37Rv in both human and murine macrophages. We further demonstrated that Amoxapine induces autophagy by inhibiting mTOR activation. Inhibition of autophagy by ATG16L1 knockdown significantly diminished intracellular killing effects of Amoxapine against BCG. In summary, our study identified Amoxapine as a novel host-directed drug that enhances the intracellular killing of mycobacteria by induction of autophagy.