Posaconazole is a potent inhibitor of sterol 14alpha-demethylation in yeasts and molds

Posaconazole (POS; SCH 56592) is a novel triazole that is active against a wide variety of fungi, including fluconazole-resistant Candida albicans isolates and fungi that are inherently less susceptible to approved azoles, such as Candida glabrata. In this study, we compared the effects of POS, itra...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2004-10, Vol.48 (10), p.3690-3696
Main Authors: Munayyer, Hanan K, Mann, Paul A, Chau, Andrew S, Yarosh-Tomaine, Taisa, Greene, Jonathan R, Hare, Roberta S, Heimark, Larry, Palermo, Robert E, Loebenberg, David, McNicholas, Paul M
Format: Article
Language:English
Subjects:
Antifungal Agents - pharmacology
Aspergillus flavus - drug effects
Aspergillus flavus - metabolism
Aspergillus fumigatus - drug effects
Aspergillus fumigatus - metabolism
Azoles - pharmacology
Candida glabrata - drug effects
Candida glabrata - metabolism
Chromatography, High Pressure Liquid
Cytochrome P-450 Enzyme Inhibitors
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Ergosterol - metabolism
Gas Chromatography-Mass Spectrometry
Microbial Sensitivity Tests
Oxidoreductases - antagonists & inhibitors
Sterol 14-Demethylase
Triazoles - pharmacology
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Summary:Posaconazole (POS; SCH 56592) is a novel triazole that is active against a wide variety of fungi, including fluconazole-resistant Candida albicans isolates and fungi that are inherently less susceptible to approved azoles, such as Candida glabrata. In this study, we compared the effects of POS, itraconazole (ITZ), fluconazole (FLZ), and voriconazole (VOR) on sterol biosynthesis in strains of C. albicans (both azole-sensitive and azole-resistant strains), C. glabrata, Aspergillus fumigatus, and Aspergillus flavus. Following exposure to azoles, nonsaponifiable sterols were extracted and resolved by liquid chromatography and sterol identity was confirmed by mass spectroscopy. Ergosterol was the major sterol in all but one of the strains; C. glabrata strain C110 synthesized an unusual sterol in place of ergosterol. Exposure to POS led to a decrease in the total sterol content of all the strains tested. The decrease was accompanied by the accumulation of 14alpha-methylated sterols, supporting the contention that POS inhibits the cytochrome P450 14alpha-demethylase enzyme. The degree of sterol inhibition was dependent on both dose and the susceptibility of the strain tested. POS retained activity against C. albicans isolates with mutated forms of the 14alpha-demethylase that rendered these strains resistant to FLZ, ITZ, and VOR. In addition, POS was a more potent inhibitor of sterol synthesis in A. fumigatus and A. flavus than either ITZ or VOR.
ISSN:0066-4804