Kinase Inhibitor Library Screening Identifies the Cancer Therapeutic Sorafenib and Structurally Similar Compounds as Strong Inhibitors of the Fungal Pathogen Histoplasma capsulatum

Abstract

Histoplasma capsulatum is a dimorphic fungal pathogen endemic to the midwestern and southern United States. It causes mycoses ranging from subclinical respiratory infections to severe systemic disease, and is of particular concern for immunocompromised patients in endemic areas. Clinical management of histoplasmosis relies on protracted regimens of antifungal drugs whose effectiveness can be limited by toxicity. In this study, we hypothesize that conserved biochemical signaling pathways in the eukaryotic domain can be leveraged to repurpose kinase inhibitors as antifungal compounds. We conducted a screen of two kinase inhibitor libraries to identify compounds inhibiting the growth of Histoplasma capsulatum in the pathogenic yeast form. Our approach identified seven compounds with an elongated hydrophobic polyaromatic structure, five of which share a molecular motif including a urea unit linking a halogenated benzene ring and a para-substituted polyaromatic group. The top hits include the cancer therapeutic Sorafenib, which inhibits growth of Histoplasma in vitro and in a macrophage infection model with low host cell cytotoxicity. Our results reveal the possibility of repurposing Sorafenib or derivatives thereof as therapy for histoplasmosis, and suggest that repurposing of libraries developed for human cellular targets may be a fruitful source of antifungal discovery.