Mechanism of the synergistic effect of amiodarone and fluconazole in Candida albicans

Soledad Gamarra, Elousa Maria F Rocha, Yong Qiang Zhang, Steven Park, Rajini Rao, David S. Perlin

Research output: Contribution to journalArticle

Abstract

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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)1753-1761
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume54
Issue number5
DOIs
StatePublished - May 2010

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Amiodarone
Fluconazole
Candida albicans
Ergosterol
Genes
Drug Synergism
Candidiasis
Calcineurin
Anti-Arrhythmia Agents
Gene Expression Profiling
Morphogenesis
Cell Wall
Virulence
Saccharomyces cerevisiae
Homeostasis
Transcription Factors
Down-Regulation
Calcium
Gene Expression

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Mechanism of the synergistic effect of amiodarone and fluconazole in Candida albicans. / Gamarra, Soledad; Rocha, Elousa Maria F; Zhang, Yong Qiang; Park, Steven; Rao, Rajini; Perlin, David S.

In: Antimicrobial Agents and Chemotherapy, Vol. 54, No. 5, 05.2010, p. 1753-1761.

Research output: Contribution to journalArticle

Gamarra, Soledad ; Rocha, Elousa Maria F ; Zhang, Yong Qiang ; Park, Steven ; Rao, Rajini ; Perlin, David S. / Mechanism of the synergistic effect of amiodarone and fluconazole in Candida albicans. In: Antimicrobial Agents and Chemotherapy. 2010 ; Vol. 54, No. 5. pp. 1753-1761.
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