The repurposed STAT3 inhibitor pyrimethamine controls mycobacterial infection-induced vascular permeability and mycobacterial burden

Infection-induced vascular pathologies are a side effect of the immune response to contact with a range of pathogens. Mycobacteria, including Mycobacterium tuberculosis, are particularly adept at co-opting vascular leakiness as a survival mechanism to shape the host immune response and impede the delivery of antibiotics to sites of infection. Here using the zebrafish-Mycobacterium marinum infection model, we confirm a critical role for Signal transducer and activator of transcription 3 (STAT3) in mediating infection-induced vascular permeability, and demonstrate the ability of FDA-approved drugs atovaquone (Mepron) and pyrimethamine (Daraprim) to restore vascular barrier function without compromising innate immune control of mycobacterial infection. We find an additional antibiotic effect of pyrimethamine against M. marinum and M. tuberculosis. Together our findings suggest pyrimethamine could be used as adjunctive therapy against mycobacterial infection and explain the protective effect of Daraprim prophylaxis against tuberculosis diagnosis in HIV positive populations.