Characterization of a novel, broad-based fungicidal activity for the antiarrhythmic drug amiodarone
Characterization of a novel, broad-based fungicidal activity for the antiarrhythmic drug amiodarone
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DOI：
10.1124/jpet.300.1.195
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发表时间：
2002-01-01
影响因子：
3.5
通讯作者：
Courchesne, WE
中科院分区：
文献类型：
--
作者：
Courchesne, WE
真菌感染在获得性免疫缺陷综合征患者中很常见，并构成一个主要的健康管理问题。需要鉴定新的抗真菌剂以补充有限的现有库并对抗新出现的耐药性真菌菌株。我们已经确定了一种新的抗真菌活性的抗真菌药物胺碘酮。对该活性的广泛表征表明，胺碘酮对几种不同的真菌表现出生长抑制作用，包括隐球菌属、酵母属、曲霉属、念珠菌属和镰刀菌属。抗真菌活性被证明是杀真菌的;用胺碘酮治疗的新型隐球菌在药物暴露数小时内失去活力。生长抑制可以通过向培养基中加入非常高浓度（10 mM）的钙来抑制，这表明钙稳态的破坏参与了抗真菌活性。放射性标记的钙外排的直接测量表明，胺碘酮的加入导致细胞钙的立即外排。总之，胺碘酮显示出广泛的杀真菌活性，可能部分通过扰乱钙平衡发挥作用。
Fungal infections are common in patients with acquired immunodeficiency syndrome and pose a major health management problem. There is a need for identification of new antifungals to complement the limited current repertoire and to combat newly arising resistant fungal strains. We have identified a novel antifungal activity for the antiarrhythmic drug amiodarone. Extensive characterization of this activity shows that amiodarone exhibits a growth inhibition for several diverse fungi, including species of Cryptococcus, Saccharomyces, Aspergillus, Candida, and Fusarium. The antifungal activity was shown to be fungicidal; Cryptococcus neoformans treated with amiodarone lost viability within hours of drug exposure. Growth inhibition could be suppressed by addition of very high concentrations (10 mM) of calcium to the medium, suggesting that disruption of calcium homeostasis was involved in the antifungal activity. Direct measurement of radiolabeled calcium efflux showed that addition of amiodarone resulted in an immediate efflux of cellular calcium. In conclusion, amiodarone displays broad-based fungicidal activity and may be acting in part by perturbing the calcium balance.