MECHANISM OF FLUCONAZOLE RESISTANCE IN CANDIDA-KRUSEI

The mechanisms of fluconazole resistance in three clinical isolates of Candida krusei were investigated. Analysis of sterols of organisms gr own in the absence and presence of fluconazole demonstrated that the p redominant sterol of C. krusei is ergosterol and that fluconazole inhi bits 14 alpha-demethylase in this organism. The 14 alpha-demethylase a ctivity in cell extracts of C, krusei was 16- to 46-fold more resistan t to inhibition by fluconazole than was 14a-demethylase activity in ce ll extracts of two fluconazole-susceptible strains of Candida albicans , Comparing the carbon monoxide difference spectra of microsomes from C, krusei with those of microsomes from C, albicans indicated that the total cytochrome P-450 content of C, krusei is similar to that of C, albicans, The Soret absorption maximum in these spectra was located at 448 nm for C, krusei and at 450 nm for C, albicans, Finally, the fluc onazole accumulation of two of the C. krusei isolates was similar to i f not greater than that of C, albicans, Thus, there are significant qu alitative differences between the 14 alpha-demethylase of C. albicans and C, krusei, In addition, fluconazole resistance in these strains of C. krusei appears to be mediated predominantly by a reduced susceptib ility of 14 alpha-demethylase to inhibition by this drug.