| Summary: | Even though Everolimus has been investigated in a phase II randomized trial as a host-directed therapy (HDT) to treat tuberculosis (TB), an oncological patient treated with Everolimus for a neuroendocrine pancreatic neoplasia developed active TB twice and a non-tuberculous mycobacterial (NTM) infection in a year and a half time span. To investigate this interesting case, we isolated and genotypically characterized the <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) clinical strain from the patient and tested the effect of Everolimus on its viability in an axenic culture and in a peripheral blood mononuclear cell (PBMCs) infection model. To exclude strain-specific resistance, we tested the activity of Everolimus against <i>Mtb</i> strains of ancient and modern lineages. Furthermore, we investigated the Everolimus effect on ROS production and autophagy modulation during <i>Mtb</i> infection. Everolimus did not have a direct effect on mycobacteria viability and a negligible effect during <i>Mtb</i> infection in host cells, although it stimulated autophagy and ROS production. Despite being a biologically plausible HDT against TB, Everolimus does not exert a direct or indirect activity on <i>Mtb</i>. This case underlines the need for a careful approach to drug repurposing and implementation and the importance of pre-clinical experimental studies.
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