INHIBITION OF STEROL 4-DEMETHYLATION IN CANDIDA-ALBICANS BY 6-AMINO-2-N-PENTYLTHIOBENZOTHIAZOLE, A NOVEL MECHANISM OF ACTION FOR AN ANTIFUNGAL AGENT

The effects of 6-amino-2-n-pentylthiobenzothiazole (APB), a new antifu ngal agent, on ergosterol biosynthesis in Candida albicans and Sacchar omyces cerevisiae were studied, using [C-14] acetate incorporation. I n C. albicans, the inhibition of growth was accompanied by a marked in hibition of acetate incorporation in 4-desmethylsterols, with a signif icant portion of the radiolabel being incorporated in 4,4-dimethylster ol lanosterol, and 4,4-dimethylzymosterol and minor amounts being inco rporated in 4-methylsterols and squalene. The data are interpreted as evidence of a block of the ergosterol biosynthesis pathway at the leve l of 4-demethylation of 4,4-dimethylzymosterol, with partial inhibitio n of lanosterol 14-demethylation and squalene epoxidation also being p ossible. In 6-amino-2-n-pentylthiobenzothiazole-treated S. cerevisiae, a significant amount of the radio-label was incorporated also in 4-me thylsterol, 3-methylzymosterol, and 4-methylfecosterol indicating that in this microorganism there are different sensitivities of the two 4- demethylations and that the pathway is blocked at the level of 4-demet hylation of 4-methylsterols.