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.

Identifying Potential Molecular Targets in Fungi Based on (Dis)Similarities in Binding Site Architecture with Proteins of the Human Pharmacolome

“…Several of the human proteins included in Table 1 are the targets of drugs and inhibitors that have been tested in fungi. For example, the cancer drug sorafenib, which targets multiple proteins, among them the P-glycoprotein 1 (P08183), was identified from a kinase inhibitor library screening as a strong inhibitor of Histoplasma capsulatum and Cryptococcus neoformans [ 28 ]. Statins such as atorvastatin and simvastatin, targeting the HMG-CoA reductase (P04035) have shown inhibitory effects in Candida albicans , Candida Glabrata and Aspergillus fumigatus [ 29 ].…”

Mebendazole Inhibits Histoplasma capsulatum In Vitro Growth and Decreases Mitochondrion and Cytoskeleton Protein Levels

“…A more accessible alternative is drug repurposing, a strategy to identify new uses for existing and marketed drugs for treatments different from those initially described [ 41 ]. Some studies point to promising drug repurposing results for Histoplasma [ 19 , 20 ], Cryptococcus [ 26 , 42 ], and Paracoccidioides infections [ 43 ]. In fact, due to the paucity of currently approved antifungal drugs, more repurposing studies for these life-threatening pathogens are necessary.…”

“…Studies involving drug repurposing to improve the therapeutic arsenal for histoplasmosis point to sorafenib, an antineoplastic agent indicated for the treatment of renal carcinoma, as a promising candidate. This drug inhibited Histoplasma growth in vitro and in a macrophage infection model with low host cell cytotoxicity [ 19 ]. Another study points to nitrofuran and indole derivatives as promising drugs for histoplasmosis treatment [ 20 ].…”