Mechanism of the synergistic effect of amiodarone and fluconazole in Candida albicans.
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.
Gamarra
Soledad
S
Public Health Research Institute, New Jersey Medical School-UMDNJ, Newark, NJ 07103-3535, USA.
Rocha
Elousa Maria F
EM
Zhang
Yong-Qiang
YQ
Park
Steven
S
Rao
Rajini
R
Perlin
David S
DS
D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D015536:Down-Regulation / Q000187:drug effects; D025141:Drug Resistance, Fungal / Q000502:physiology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004875:Ergosterol / Q000378:metabolism; D005260:Female; D015725:Fluconazole / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005800:Genes, Fungal / Q000187:drug effects / Q000235:genetics; D025301:Hyphae / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015854:Up-Regulation / Q000187:drug effects; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D015725:Fluconazole; D000638:Amiodarone; D002118:Calcium; D004875:Ergosterol