Evaluation of Everolimus Activity against <i>Mycobacterium tuberculosis</i> Using In Vitro Models of Infection

• Main Authors: Delia Mercedes Bianco (Author), Flavio De Maio (Author), Giulia Santarelli (Author), Ivana Palucci (Author), Alessandro Salustri (Author), Giada Bianchetti (Author), Giuseppe Maulucci (Author), Franco Citterio (Author), Maurizio Sanguinetti (Author), Enrica Tamburrini (Author), Michela Sali (Author), Giovanni Delogu (Author)
• Format: Book
• Published: MDPI AG, 2023-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics12010171; 2079-6382
• Keywords: latent tuberculosis infection; host-directed therapies; Everolimus; mTOR inhibitors; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 12, Iss 1, p 171 (2023)

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.