Effects of antifungal agents on ergosterol biosynthesis in Candida albicans and Trichophyton mentagrophytes: differential inhibitory sites of naphthiomate and miconazole

Abstract

The effects of naphthiomate and miconazole showing ergosterol biosynthesis inhibition on Candida albicans and Trichophyton mentagrophytes were investigated by measuring [14C]acetate incorporation into sterols and its precursors. Naphthiomate, like allylamine compounds, was found to interfere with fungal ergosterol biosynthesis by preventing the conversion of squalene into squalene epoxide which is mediated by squalene epoxidase. This metabolic inhibition resulted in a considerable decrease of ergosterol with a corresponding increase of squalene, which is more distinct in T. mentagrophytes than in C. albicans. This indicates that naphthiomate blocks the utilization of squalene by inhibition of squalene epoxidation; unlike N-substituted imidazole, miconazole has been known to inhibit ergosterol formation by inhibiting C14-demethylation. In addition, it is of interest to note that miconazole causes a great accumulation of lanosterol in C. albicans cells, while in T. mentagrophytes cells there was instead a drastic increase of 24-methylenedihydrolanosterol but not lanosterol. The results obtained from this study indicate that repression of ergosterol synthesis by naphthiomate and miconazole is due to inhibition of squalene epoxidation for the former and C14-demethylation for the latter.