新型Arylamidine T-2307通过抑制呼吸链复合物选择性破坏酵母线粒体功能。,Antimicrobial Agents and Chemotherapy

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新型Arylamidine T-2307通过抑制呼吸链复合物选择性破坏酵母线粒体功能。
Antimicrobial Agents and Chemotherapy ( IF 4.1 ) Pub Date : 2019-07-25 , DOI: 10.1128/aac.00374-19
Kohei Yamashita _{1,

2} , Taiga Miyazaki _{3,

4} , Yoshiko Fukuda ₅ , Junichi Mitsuyama ₆ , Tomomi Saijo ₇ , Shintaro Shimamura ₇ , Kazuko Yamamoto ₇ , Yoshifumi Imamura ₇ , Koichi Izumikawa ₄ , Katsunori Yanagihara ₈ , Shigeru Kohno ₇ , Hiroshi Mukae _{2,

7}

Affiliation

新型芳胺T-2307对临床上重要的病原体具有广谱的体外和体内抗真菌活性。先前的研究表明，T-2307通过特定的多胺转运蛋白在酵母细胞中积累，并破坏酵母线粒体膜电位。此外，它对大鼠肝线粒体功能几乎没有影响。T-2307破坏酵母线粒体功能的机制了解甚少，其阐明可能为开发新型抗真菌剂提供重要信息。这项研究旨在确定T-2307如何促进酵母线粒体功能障碍，并研究真菌与哺乳动物之间这种机制的选择性。T-2307以剂量依赖性方式抑制酵母全细胞和分离的酵母线粒体的呼吸。T-2307和呼吸链抑制剂对线粒体呼吸作用的相似性促使我们研究T-2307对线粒体呼吸链复合物的作用。T-2307不仅在酿酒酵母中而且在白色念珠菌中特别抑制呼吸链复合物III和IV，这表明T-2307以类似于酵母的方式对抗病原性真菌。相反，T-2307对牛呼吸链复合物几乎没有影响。此外，我们证明了T-2307对呼吸链复合物的抑制作用导致酵母细胞内细胞内ATP水平的降低。这些结果表明，抑制呼吸链复合物III和IV是选择性破坏酵母线粒体功能和抗真菌活性的关键因素。

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The Novel Arylamidine T-2307 Selectively Disrupts Yeast Mitochondrial Function by Inhibiting Respiratory Chain Complexes.

The novel arylamidine T-2307 exhibits broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. Previous studies have shown that T-2307 accumulates in yeast cells via a specific polyamine transporter and disrupts yeast mitochondrial membrane potential. Further, it has little effect on rat liver mitochondrial function. The mechanism by which T-2307 disrupts yeast mitochondrial function is poorly understood, and its elucidation may provide important information for developing novel antifungal agents. This study aimed to determine how T-2307 promotes yeast mitochondrial dysfunction and to investigate the selectivity of this mechanism between fungi and mammals. T-2307 inhibited the respiration of yeast whole cells and isolated yeast mitochondria in a dose-dependent manner. The similarity of the effects of T-2307 and respiratory chain inhibitors on mitochondrial respiration prompted us to investigate the effect of T-2307 on mitochondrial respiratory chain complexes. T-2307 particularly inhibited respiratory chain complexes III and IV not only in Saccharomyces cerevisiae but also in Candida albicans, indicating that T-2307 acts against pathogenic fungi in a manner similar to that of yeast. Conversely, T-2307 showed little effect on bovine respiratory chain complexes. Additionally, we demonstrated that the inhibition of respiratory chain complexes by T-2307 resulted in a decrease in the intracellular ATP levels in yeast cells. These results indicate that inhibition of respiratory chain complexes III and IV is a key factor for selective disruption of yeast mitochondrial function and antifungal activity.

更新日期：2019-11-01

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