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Antimicrobial Agents and Chemotherapy, October 2004, p. 3690-3696, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3690-3696.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Posaconazole Is a Potent Inhibitor of Sterol 14{alpha}-Demethylation in Yeasts and Molds

Hanan K. Munayyer,{dagger} Paul A. Mann,{dagger} Andrew S. Chau, Taisa Yarosh-Tomaine, Jonathan R. Greene, Roberta S. Hare, Larry Heimark, Robert E. Palermo, David Loebenberg, and Paul M. McNicholas*

Schering-Plough Research Institute, Kenilworth, New Jersey

Received 4 March 2004/ Returned for modification 30 April 2004/ Accepted 18 June 2004

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 14{alpha}-methylated sterols, supporting the contention that POS inhibits the cytochrome P450 14{alpha}-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 14{alpha}-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.

* Corresponding author: Mailing address: Schering-Plough Research Institute, 2015 Galloping Hill Rd., K15-4-4700, Kenilworth, NJ 07033. Phone: (908) 740-7644. Fax: (908) 740-3918. E-mail: paul.mcnicholas{at}spcorp.com.

{dagger} H.K.M. and P.A.M. contributed equally to this work.

Antimicrobial Agents and Chemotherapy, October 2004, p. 3690-3696, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3690-3696.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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