Mechanism of the Synergistic Effect of Amiodarone and Fluconazole in Candida albicans
Mechanism of the Synergistic Effect of Amiodarone and Fluconazole in Candida albicans
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DOI：
10.1128/aac.01728-09
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发表时间：
2010-05-01
影响因子：
4.9
通讯作者：
Perlin, David S.
中科院分区：
文献类型：
--
作者：
Gamarra, Soledad;Rocha, Elousa Maria F.;Perlin, David S.
抗心律失常药物胺碘酮已被发现具有杀菌活性。在酿酒酵母中，其抗真菌活性是由钙超载胁迫介导的，导致钙调神经磷酸酶调节的转录因子CRZ1的快速核积累。此外，据报道，在对氟康唑耐药的白色念珠菌中，低剂量的胺碘酮与氟康唑有协同作用。为了确定其对白色念珠菌的毒性机制，我们利用关键途径基因的表达谱检测了胺碘酮单独和与氟康唑联合使用时的细胞反应。对胺碘酮和/或氟康唑暴露后的5株白色念珠菌(3株氟康唑敏感株和2株氟康唑耐药株)的59个基因进行了基因表达谱分析。在59个基因中，有27个基因的表达水平在胺碘酮暴露后发生了显著变化(>；2倍)。上调或下调的基因包括与钙离子稳态、细胞壁合成、空泡/溶酶体运输、多种途径调节、胁迫反应和假菌丝形态发生有关的基因。正如预期的那样，氟康唑诱导麦角固醇途径基因表达水平增加。联合治疗显著抑制了对任何一种药物的转录反应，表明协同作用是由于抑制了代偿反应途径。这种抑制导致总麦角甾醇水平下降和假菌丝形成减少，这一发现与小鼠念珠菌病模型中毒力下降的发现一致。
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.