No abstract

A human fungal pathogen, Candida albicans, varies from the yeast form to the hyphal form due to various external signals. This morphogenetic transformation has been implicated in the development of pathogenicity. In this report, we show that calmodulin inhibitors (TFP and W-7) and an adenylatecyclase inhibitor (MDL-12-330A) suppressed the hyphae formation of C. albicans. Furthermore, the expression of hyphae-specific mRNAs located downstream from the RAS1-cAMP pathway was inhibited by these inhibitors. Suppression of hyphae formation by TFP or W-7 was not inhibited by the addition of cAMP, and these inhibitors did not affect the amount of cAMP in C. albicans. These results suggest that the Ca2+/calmodulin pathway contributes to hyphae formation and is related to the RAS1-cAMP pathway.

Candida albicans undergoes a yeast-to-hyphal transition that has been recognized as a virulence property as well as a turning point leading to biofilm formation associated with candidiasis. It is known that yeast-to-hyphal transition is induced under complex environmental conditions including temperature (above 35°C), pH (greater than 6.5), CO2, N-acetylglucosamine (GlcNAc), amino acids, RPMI-1640 synthetic culture medium, and blood serum. To identify the hyphal induction factor in the RPMI-1640 medium, we examined each component of RPMI-1640 and established a simple hyphal induction condition, that is, incubation in L-proline solution at 37°C. Incubation in GlcNAc solution alone, which is not contained in RPMI-1640, without any other materials was also identified as another simple hyphal induction condition. To inhibit hyphal formation, proline and GlcNAc analogs were examined. Among the proline analogs used, L-azetidine-2-carboxylic acid (AZC) inhibited hyphal induction under both induction conditions, but L-4-thiazolidinecarboxylic acid (T4C) specifically inhibited proline-induced hyphal formation only, while α-N-methyl-L-proline (mPro) selectively inhibited GlcNAc-induced hyphal formation. Hyphal formation in fetal bovine serum was also inhibited by AZC or T4C together with mPro without affecting the proliferation of yeast form. These results indicate that these proline analogs are ideal inhibitors of yeast-to-hyphal transition in C. albicans.