title: Posaconazole is a potent inhibitor of sterol 14alpha-demethylation in yeasts and molds.
abstract: 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.
authors.affiliation: Mailing address: Schering-Plough Research Institute, 2015 Galloping Hill Rd., K15-4-4700, Kenilworth, NJ 07033. paul.mcnicholas@spcorp.com
authors.forename: Hanan K
authors.initials: HK
authors.lastname: Munayyer
authors.forename: Paul A
authors.initials: PA
authors.lastname: Mann
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chau
authors.forename: Taisa
authors.initials: T
authors.lastname: Yarosh-Tomaine
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Greene
authors.forename: Roberta S
authors.initials: RS
authors.lastname: Hare
authors.forename: Larry
authors.initials: L
authors.lastname: Heimark
authors.forename: Robert E
authors.initials: RE
authors.lastname: Palermo
authors.forename: David
authors.initials: D
authors.lastname: Loebenberg
authors.forename: Paul M
authors.initials: PM
authors.lastname: McNicholas
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001231:Aspergillus flavus / Q000187:drug effects / Q000378:metabolism*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000378:metabolism*; D001393:Azoles / Q000494:pharmacology; D041221:Candida glabrata / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004875:Ergosterol / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D008826:Microbial Sensitivity Tests; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D058886:Sterol 14-Demethylase; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D014230:Triazoles; C101425:posaconazole; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D004875:Ergosterol