Mechanism of the Synergistic Effect of Amiodarone and Fluconazole in Candida albicans
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The antiarrhythmic drug amiodarone has been found to have fungicidal activity. In Saccharomyces cerevisiae , its antifungal activity is mediated by calcium overload stress, which leads to a rapid nuclear accumulation of the calcineurin-regulated transcription factor CRZ1 . In addition, low doses of amiodarone have been reported to be synergistic with fluconazole in fluconazole-resistant Candida albicans . To establish its mechanism of toxicity in C. albicans , we used expression profiling of key pathway genes to examine cellular responses to amiodarone alone and in combination with fluconazole. Gene expression profiling of 59 genes was done in five C. albicans strains (three fluconazole-susceptible strains and two fluconazole-resistant strains) after amiodarone and/or fluconazole exposure. Of the 59 genes, 27 analyzed showed a significant change (>2-fold) in expression levels after amiodarone exposure. The up- or downregulated genes included genes involved in Ca 2+ homeostasis, cell wall synthesis, vacuolar/lysosomal transport, diverse pathway regulation, stress response, and pseudohyphal morphogenesis. As expected, fluconazole induces an increase in ergosterol pathway genes expression levels. The combination treatment significantly dampened the transcriptional response to either drug, suggesting that synergism was due to an inhibition of compensatory response pathways. This dampening resulted in a decrease in total ergosterol levels and decreased pseudohyphal formation, a finding consistent with decreased virulence in a murine candidiasis model.
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The primary screen identified several drugs with known fluconazole chemosensitizing activities, including simvastatin, atorvastatin, lovastatin, artemisinin, amiodarone, sulfamethoxazole, doxycycline, nisoldipine, and tamoxifen.
“In addition and as expected, the primary screen identified several drugs with known fluconazole chemosensitizing activities, such as the cholesterol-lowering agents; simvastatin, atorvastatin, and lovastatin, artemisinin, amiodarone, sulfamethoxazole, doxycycline, and the calcineurin inhibitors nisoldipine and tamoxifen19–25.”
From Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species (2020) · cites this paper as [24]
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- Authors
- Gamarra, S., Rocha, E. M. F., Zhang, Y.-Q., Park, S., Rao, R., & Perlin, D. S.
- Affiliations
- Rutgers New Jersey Medical School (US)
- Johns Hopkins University (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2010-05
- Volume
- 54
- Issue
- 5
- Pages
- 1753-1761
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC2863688
- OpenAlex
- W2160533977
- Cited by
- 70
- References
- 54
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 7 · 2020: 1 · 2019: 5 · 2018: 5 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 6 · 2013: 10 · 2012: 9
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI069397, AI065983, R01AI069397, R01AI065983)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- amiodarone, fluconazole, Candida albicans, drug synergy, antifungal activity, fluconazole resistance, calcium homeostasis, ergosterol biosynthesis, gene expression profiling, calcineurin
- MeSH terms
- Amiodarone, Animals, Antifungal Agents, Calcium, Candida albicans, Candidiasis, Drug Synergism, Enzyme Inhibitors, Ergosterol, Female, Genes, Fungal, Lysosomes, Mice, Inbred BALB C, Vacuoles, Down-Regulation, Fluconazole, Up-Regulation, Gene Expression Profiling, Drug Resistance, Fungal, Hyphae, Mice
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