This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xiong, Q. Articles by Matsuda, S. P. T. Search for Related Content PubMed PubMed Citation Articles by Xiong, Q. Articles by Matsuda, S. P. T.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, February 2005, p. 518-524, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.518-524.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cholesterol Import by Aspergillus fumigatus and Its Influence on Antifungal Potency of Sterol Biosynthesis Inhibitors

Department of Biochemistry and Cell Biology,¹ Department of Chemistry, Rice University,³ Department of Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas²

Received 29 May 2004/ Returned for modification 5 August 2004/ Accepted 6 October 2004

High mortality rates from invasive aspergillosis in immunocompromised patients are prompting research toward improved antifungal therapy and better understanding of fungal physiology. Herein we show that Aspergillus fumigatus, the major pathogen in aspergillosis, imports exogenous cholesterol under aerobic conditions and thus compromises the antifungal potency of sterol biosynthesis inhibitors. Adding serum to RPMI medium led to enhanced growth of A. fumigatus and extensive import of cholesterol, most of which was stored as ester. Growth enhancement and sterol import also occurred when the medium was supplemented with purified cholesterol instead of serum. Cells cultured in RPMI medium with the sterol biosynthesis inhibitors itraconazole or voriconazole showed retarded growth, a dose-dependent decrease in ergosterol levels, and accumulation of aberrant sterol intermediates. Adding serum or cholesterol to the medium partially rescued the cells from the drug-induced growth inhibition. We conclude that cholesterol import attenuates the potency of sterol biosynthesis inhibitors, perhaps in part by providing a substitute for membrane ergosterol. Our findings establish significant differences in sterol homeostasis between filamentous fungi and yeast. These differences indicate the potential value of screening aspergillosis antifungal agents in serum or other cholesterol-containing medium. Our results also suggest an explanation for the antagonism between itraconazole and amphotericin B, the potential use of Aspergillus as a model for sterol trafficking, and new insights for antifungal drug development.

This article has been cited by other articles:

• Nakayama, H., Tanabe, K., Bard, M., Hodgson, W., Wu, S., Takemori, D., Aoyama, T., Kumaraswami, N. S., Metzler, L., Takano, Y., Chibana, H., Niimi, M. (2007). The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum. J Antimicrob Chemother 60: 1264-1272 [Abstract] [Full Text]  
• Zhou, W., Cross, G. A. M., Nes, W. D. (2007). Cholesterol import fails to prevent catalyst-based inhibition of ergosterol synthesis and cell proliferation of Trypanosoma brucei. J. Lipid Res. 48: 665-673 [Abstract] [Full Text]