The interaction of azole antifungal antibiotics with purified Candida albicans cytochrome P-450-dependent 14 alpha-sterol demethylase (P-450DM) was measured spectrophotometrically and by inhibition of enzyme activity. Ketoconazole and ICI 153066 (a triazole derivative) formed low-spin complexes with the ferric cytochrome and induced type II difference spectra. These spectra are indicative of an interaction between the azole moiety and the sixth co-ordination position of P-450DM haem. Both azoles inhibited the binding of CO to the sodium dithionite-reduced ferrous cytochrome, and inhibited reconstituted P-450DM activity by binding to the cytochrome with a one-to-one stoichiometry. Similarly, total inhibition of enzyme activity occurred when equimolar amounts of clotrimazole, miconazole or fluconazole were added to reconstituted P-450DM. These results correlated with the inhibition of P-450DM in broken cell preparations, confirming that all five azoles are potent inhibitors of ergosterol biosynthesis in C. albicans.
Interaction of azole antifungal antibiotics with cytochrome P-450-dependent 14α-sterol demethylase purified from Candida albicans
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C A Hitchcock, K Dickinson, S B Brown, E G V Evans, D J Adams; Interaction of azole antifungal antibiotics with cytochrome P-450-dependent 14α-sterol demethylase purified from Candida albicans. Biochem J 1 March 1990; 266 (2): 475–480. doi: https://doi.org/10.1042/bj2660475
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