Inhibition of Ras1-MAPK pathways for hypha formation by novel drug candidates in Candida albicans

Abstract

The opportunistic human fungal pathogen Candida albicans has morphogenesis as a virulence factor. The morphogenesis of C. albicans is closely related to pathogenicity. Ras1 in C. albicans is an important switch in the MAPK pathway for morphogenesis. The MAPK pathway is important for the virulence, such as cell growth, morphogenesis, and biofilm formation. Ume6 is a well-known transcriptional factor for hyphal-specific genes. Despite numerous studies, as a recent issue, it is necessary to develop a new drug that uses a different pathway mechanism to inhibit resistant C. albicans strains caused by chronic prescription of azole or echinocandin drugs, which are mainly used. Here, we show that the small carbazole derivatives attenuated the pathogenicity of C. albicans through inhibition of the Ras1/MAPK pathway. We found that the small molecules inhibit morphogenesis through repressing protein and RNA levels in Ras/MAPK related genes including UME6 and NRG1 . Furthermore, we found the antifungal effect of the small molecules in vivo using a candidiasis murine model. We anticipate our findings are that the small molecules are the promising compounds for the development of new antifungal agents for the treatment of systemic candidiasis and possibly for other fungal diseases.