ROS formation is a differential contributory factor to the fungicidal action of Amphotericin B and Micafungin in Candida albicans
ROS formation is a differential contributory factor to the fungicidal action of Amphotericin B and Micafungin in Candida albicans
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DOI：
10.1016/j.ijmm.2017.03.005
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发表时间：
2017-06-01
影响因子：
4.1
通讯作者：
Arguelles, Juan-Carlos
中科院分区：
文献类型：
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作者：
Guirao-Abad, Jose P.;Sanchez-Fresneda, Ruth;Arguelles, Juan-Carlos
在白色念珠菌中，研究了活性氧簇(ROS)在两性霉素B(Amb)和米卡芬净(Mf)杀菌作用中的作用。Mf和Amb的临床MIC值分别为0.016和0.12mU g/ml。在白念珠菌SC5314菌株中，AMB(0.5-1.0xMIC)诱导产生显著的ROS并伴有高度的细胞杀伤，而MF的杀菌作用仍然有效，但ROS的产生很少。用硫脲预先孵育可抑制ROS的形成，并导致细胞活力显著增加，无论使用何种抗真菌药物。对几种成熟的抗氧化酶(过氧化氢酶、谷胱甘肽还原酶和超氧化物歧化酶)的同时测定表明，AMB对这三种酶的活性有很强的诱导作用，而MF只有很弱的刺激作用。同样，AMB而不是MF促进了线粒体膜电位的显著上升以及细胞内海藻糖的合成，海藻糖是一种非还原双糖，在白色念珠菌中起到了对抗氧化应激的特殊保护作用。光学和电子显微镜分析显示，这两种抗真菌药物对细胞完整性和结构改变都有显著的破坏作用。综上所述，我们的结果强烈表明，通过积累ROS在白色念珠菌中诱导内部氧化应激是一种广泛使用的多烯(Amb)而不是MF(棘球菌素)的抗真菌作用的优先贡献因素。
The hypothetical role played by the intracellular formation of reactive oxygen species (ROS) in the fungicidal action carried out by Amphotericin B (AmB) and Micafungin (MF) was examined in Candida albicans, which remains the most prevalent fungal pathogen. The clinical MICs for MF and AmB were 0.016 and 0.12 mu g/ml, respectively. Whereas AmB (0.5-1.0 x MIC) induced a marked production of intracellular ROS accompanied by a high degree of cell killing in the C. albicans SC5314 strain, the fungicidal effect of MF was still operative, but ROS generation was slight. Preincubation with thiourea suppressed the formation of ROS and caused a marked increase in cell viability, regardless of the antifungal used. Simultaneous measurement of several well established antioxidant enzymes (catalase, glutathione reductase and superoxide dismutase) revealed strong AmB-induced activation of the three enzymatic activities, whereas MF only had a weak stimulating effect. Likewise, AmB but not MF promoted a conspicuous rise in the mitochondrial membrane potential together with the intracellular synthesis of trehalose, the non-reducing disaccharide which acts as a specific protector against oxidative stress in C. albicans. Optical and electronic microscopy analysis revealed a significant damage to cell integrity and structural alterations caused by both antifungals. Taken together, our results strongly suggest that the induction of an internal oxidative stress in C. albicans through the accumulation of ROS is a preferential contributory factor to the antifungal action of a widely used polyene (AmB) but not of MF (echinocandin).