Genetic and physiological analysis of azole sensitivity in Saccharomyces cerevisiae

Ketoconazole and fluconazole are azole antifungal agents which inhibit cytochrome P-450 mediated sterol C14 demethylation during ergosterol biosynthesis. We report on the activity of these antifungals on a variety of Saccharomyces cerevisiae strains grown under differing conditions known to affect cyt P-450 levels. Only slight increases in resistance to azoles were observed under conditions which induce the yeast cyt P-450 from undetectable levels. Strain variation was observed, with some strains exhibiting a fungicidal, and others a fungistatic response. Two cyt P-450 deficient mutants examined exhibited resistance to treatment with fluconazole and ketoconazole. This was attributed, at least in part, to an additional defect in sterol delta 5,6 desaturation and possibly to reduced cellular levels of azole drug.