Antifungal activities of Equol against <i>Candida albicans in vitro</i> and <i>in vivo</i>

<i>Candida albicans</i> is an opportunistic fungal pathogen that can cause systemic infections in immunocompromised individuals. Morphological transition and biofilm formation are major virulence factors of <i>C. albicans</i>. Moreover, biofilm enhances resistance to antifungal agents. Therefore, it is urgent to identify new and effective compounds to target the biofilm of <i>C. albicans</i>. In the present study, the antifungal activities of equol against <i>C. albicans</i> were investigated. <i>In vitro</i>, the microdilution analysis and spot assay result showed that equol exhibited potent inhibitory activities against <i>C. albicans</i>. Further investigations confirmed that the antifungal effects of equol involved interference with the transition from yeast to hypha and biofilm formation of <i>C. albicans</i>. In addition, transcriptome sequencing and reverse transcription-quantitative PCR (qRT-PCR) analysis showed that equol significantly downregulated the expression of several genes in the Ras1-cAMP-PKA pathway related to hyphae and biofilm formation and significantly upregulated the expression of the negative transcriptional repressors <i>RFG1</i> and <i>TUP1</i>. Moreover, equol effectively reduced the production of cAMP, a key messenger in the Ras1-cAMP-PKA pathway, while supplementation with cAMP partly rescued the equol-induced defects in hyphal development. Furthermore, in a mouse model of systemic candidiasis (SC), equol treatment significantly decreased the fungal burden (liver, kidneys, and lung) in mice and local tissue damage, while enhancing the production of interleukin-10 (IL-10). Together, these findings confirm that equol is a potentially effective agent for treatment of SC.