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Genome-wide expression profiling of the response to polyene, pyrimidine, azole, and echinocandin antifungal agents in Saccharomyces cerevisiae.
Open accessAbstract
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.
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“Fungi transcriptionally upregulate expression of azole efflux pumps and ergosterol biosynthesis pathway genes when exposed to antifungal agents that target ergosterol biosynthesis.”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Agarwal et al., 2003
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“Upon azole stress, fungi can respond with a change in the transcription of a variety of genes.”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Agarwal et al., 2003
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Metadata
- Authors
- Agarwal, A. K., Rogers, P. D., Baerson, S. R., Jacob, M. R., Barker, K. S., Cleary, J. D., Walker, L. A., Nagle, D. G., & Clark, A. M.
- Affiliations
- University of Mississippi (US)
- University of Tennessee Health Science Center (US)
- Agricultural Research Service (US)
- University of Mississippi Medical Center (US)
- Corresponding author
- Agarwal, Ameeta K.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 278
- Issue
- 37
- Pages
- 34998-35015
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2106248803
- Cited by
- 204
- References
- 75
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 8 · 2019: 6 · 2018: 3 · 2017: 11 · 2016: 3 · 2015: 6 · 2014: 4 · 2013: 10 · 2012: 10
- FWCI
- 11.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Agriculture (58‐6408‐2‐0009)
- National Institutes of Health
- U.S. Public Health Service
- Agricultural Research Service (58-6408-2- 0009)
- National Institute of Allergy and Infectious Diseases (R01AI027094, R01-AI 27094, AI 27094)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
- Keywords
- antifungal agents, Saccharomyces cerevisiae, gene expression profiling, ketoconazole, amphotericin B, caspofungin, 5-fluorocytosine, polyene antibiotics, azole antifungals, echinocandins, ergosterol biosynthesis, cell wall integrity, DNA repair, cell cycle regulation, mechanism of action, antifungal drug development
- MeSH terms
- Anti-Bacterial Agents, Antifungal Agents, Azoles, Base Sequence, Ketoconazole, Peptides, Polyenes, Pyrimidines, Saccharomyces cerevisiae, Structure-Activity Relationship, Gene Expression Regulation, Fungal, Genome, Fungal, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling
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