Inhibition of Candida albicans hyphal development by sub-lethal levels of solasodine

Abstract

Opportunistic human fungal pathogen Candida albicans poses a serious health concern. It exists as part of the normal microbiota on the skin and mucosal surfaces of the mouth, digestive and urogenital systems. This unicellular microbe can be invasive and cause both superficial and disseminated infections (candidiasis) in patients with impaired immunity with high morbidity and mortality rates (40-60%). Clinical usefulness of the current limited arsenal of antifungal agents has been hampered by toxic side effects, poor pharmacokinetics, and emergence of drug-resistant isolates. One striking virulence trait of C. albicans is its ability to grow and switch between budded yeast and filamentous forms (hyphae), and it is conceivable that perturbation of hyphal development can be an attractive target in the management of candidiasis. We screened a 400-membered compound library and found that solasodine could inhibit C. albicans hyphal growth under hyphal-inducing conditions (i.e in Lee's medium at 37oC). At sub-MIC levels (≤ 60 microM), solasodine halted C. albicans yeast-to-hyphal morphological transition in a concentration-dependent manner. Physiological disturbance of cellular metabolism could be excluded as C. albicans growth was not affected. Safe concern and high selectivity of purpurin for C. albicans were justified by its non-toxic nature to primary human gingival fibroblasts and keratinocytes (2x MIC; viability = 95%). Quantitative reverse transcription-PCR analyses of hyphal specific genes indicated that solasodine upregulated the expression of TUP1 expression, but downregulated the expression of TEC1. To conclude, solasodine abrogates hyphal development in C. albicans under hyphal-inducing conditions via modulation of hyphal specific genes. Solasodine may therefore represent a potential candidate that deserves further investigations in the development of antifungal strategies against candidiasis – for example, combinational use of solasodine with antifungal agents possessing different modes of action may reduce the likelihood of acquired drug resistance.