Biochemical targets for antifungal azole derivatives: hypothesis on the mode of action.

Abstract

The selective interaction of low concentrations of azole derivatives and other nitrogen heterocycles with cytochrome P-450 may be at the origin of the inhibition of ergosterol biosynthesis. From the depletion of ergosterol and the concomitant accumulation of 14 alpha-methylsterols, alterations in membrane functions, the synthesis and activity of membrane-bound enzymes, mitochondrial activities, and an uncoordinated activation of chitin synthase may result. Since chitin synthesis is more important in the hyphal form than in the budding form of C. albicans, the uncoordinated activation of chitin synthesis may be more trouble for the hyphal growth than for yeast budding. The assumption is made that from this difference the greater sensitivity of hyphal growth to azole antifungal agents may originate. It is also assumed that the higher degree of lipid unsaturation may be related to an inhibition of ergosterol biosynthesis. The inhibition of fatty acid desaturation and elongation induced by higher doses of miconazole and ketoconazole and the longer contact times might be related to interference with membrane fluidity, or it might due to chelation of the iron used in the oxidation reduction sequence during desaturation. The decreased availability of ergosterol and the accumulation of 14 alpha-methylsterols also may provide the environment needed to inactivate membrane-bound enzymes; e.g., cytochrome c peroxidase. However, it is still too speculative to correlate effects on membrane components with miconazole-induced changes in properties of all oxidases; e.g., the NADH-dependent, cyanide-insensitive oxidase. The accumulation of toxic concentrations of hydrogen peroxide, resulting from an increased NADH-oxidase activity and disappearance of the peroxidase and catalase activity, may contribute to the degeneration of subcellular structures. The complete disappearance of catalase observed at concentrations of miconazole greater than or equal to 10(-5) M may originate from direct effects on the cell. At these high concentrations reached only by topical application, direct membrane damage resulting from interaction of miconazole with lipids was observed. These direct interactions result in an inhibition of membrane-bound enzyme and mitochondrial activities and in leakage of intracellular components. The direct interactions were much less pronounced in cells treated with ketoconazole. This correlates with the smaller area occupied in the membrane per ketoconazole molecule (30 A2), compared with that occupied in the membrane per miconazole molecule (90 A2).(ABSTRACT TRUNCATED AT 400 WORDS)