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J. Biol. Chem., Vol. 278, Issue 37, 34998-35015, September 12, 2003
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¶¶
From the
National Center for Natural Products
Research, Department of Pharmacognosy, the
Department of Pharmacology, and
¶¶Research Institute of Pharmaceutical
Sciences, University of Mississippi School of Pharmacy, University,
Mississippi 38677, the ¶Departments of Pharmacy,
Pharmaceutical Sciences and Pediatrics, Colleges of Pharmacy and Medicine,
University of Tennessee Health Science Center, Memphis, Tennessee 38163, the
||United States Department of Agriculture,
Agricultural Research Service, Natural Products Utilization Research Unit,
University, Mississippi 38677, and the **Departments
of Clinical Pharmacy Practice and Medicine, Schools of Pharmacy and Medicine,
University of Mississippi Medical Center, Jackson, Mississippi 39216
Antifungal compounds exert their activity through a variety of mechanisms, some of which are poorly understood. Novel approaches to characterize the mechanism of action of antifungal agents will be of great use in the antifungal drug development process. The aim of the present study was to investigate the changes in the gene expression profile of Saccharomyces cerevisiae following exposure to representatives of the four currently available classes of antifungal agents used in the management of systemic fungal infections. Microarray analysis indicated differential expression of 0.8, 4.1, 3.0, and 2.6% of the genes represented on the Affymetrix S98 yeast gene array in response to ketoconazole, amphotericin B, caspofungin, and 5-fluorocytosine (5-FC), respectively. Quantitative real time reverse transcriptase-PCR was used to confirm the microarray analyses. Genes responsive to ketoconazole, caspofungin, and 5-FC were indicative of the drug-specific effects. Ketoconazole exposure primarily affected genes involved in ergosterol biosynthesis and sterol uptake; caspofungin exposure affected genes involved in cell wall integrity; and 5-FC affected genes involved in DNA and protein synthesis, DNA damage repair, and cell cycle control. In contrast, amphotericin B elicited changes in gene expression reflecting cell stress, membrane reconstruction, transport, phosphate uptake, and cell wall integrity. Genes with the greatest specificity for a particular drug were grouped together as drug-specific genes, whereas genes with a lack of drug specificity were also identified. Taken together, these data shed new light on the mechanisms of action of these classes of antifungal agents and demonstrate the potential utility of gene expression profiling in antifungal drug development.
Received for publication, June 15, 2003
* This work was supported in part by a grant from the United States Public Health Service, NIAID Grant R01 AI27094 from the National Institutes of Health, the United States Department of Agriculture, Agricultural Research Service Specific Cooperative Agreement 58-6408-2-0009, and a grant from Merck. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at
http://www.jbc.org)
contains Tables A–D.
To whom correspondence should be addressed: National Center for Natural
Products Research, University, MS 38677. Tel.: 662-915-1218; Fax:
662-915-7062; E-mail:
aagarwal{at}olemiss.edu.
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