Abstract
Azole antifungal compounds are important in the treatment of Cryptococcosis, a major cause of mortality in AIDS patients. The target of the azole drugs is P450 mediated sterol 14 alpha-demethylase. We have investigated the P450 system of Cryptococcus neoformans with respect to azole tolerance observed in clinical isolates which were obtained following the failure of fluconazole therapy. The clinical failure was correlated with in vitro tolerance of azole antifungal when compared to wild-type strains. The microsomal P450 system was typical of yeast and fungi and fluconazole tolerance was not associated with defective sterol biosynthesis. The strains had slightly elevated P450 content and slightly reduced azole levels in the cells, but a clear cause for resistance was the increased level of drug needed to inhibit the sterol 14 alpha-demethylase in vitro.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AIDS-Related Opportunistic Infections / drug therapy
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AIDS-Related Opportunistic Infections / microbiology*
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Cryptococcosis / drug therapy
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Cryptococcosis / microbiology*
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Cryptococcus neoformans / chemistry
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Cryptococcus neoformans / drug effects*
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Cryptococcus neoformans / enzymology
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Cytochrome P-450 Enzyme Inhibitors*
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Cytochrome P-450 Enzyme System / biosynthesis
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Drug Resistance, Microbial
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Drug Tolerance
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Ergosterol / biosynthesis
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Fluconazole / pharmacology*
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Fluconazole / therapeutic use
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Humans
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Itraconazole / pharmacology*
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Ketoconazole / pharmacology*
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Microbial Sensitivity Tests
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Microsomes / enzymology
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Oxidoreductases / antagonists & inhibitors*
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Oxidoreductases / biosynthesis
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Sterol 14-Demethylase
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Sterols / analysis
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Treatment Failure
Substances
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CYP51A1 protein, human
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Cytochrome P-450 Enzyme Inhibitors
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Sterols
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Itraconazole
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Fluconazole
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Cytochrome P-450 Enzyme System
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Oxidoreductases
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Sterol 14-Demethylase
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Ketoconazole
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Ergosterol