新規アリールアミジンT-2307は呼吸鎖複合体阻害を介して選択的に酵母ミトコンドリアの機能を阻害する

• Main Author: 山下, 皓平
• Format: Other/Unknown Material
• Language: English
• Published: American Society for Microbiology 2020
• Subjects: Candida albicans; antifungal; mechanism of action; respiratory chain; yeast; taiga
• Online Access: https://nagasaki-u.repo.nii.ac.jp/record/69/files/ISYO59_Yamashita.pdf

Nagasaki University (長崎大学) 博士(医学) 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. 長崎大学学位論文 学位記番号:博(医歯薬)乙第59号 学位授与年月日:令和2年9月2日 Author: Kohei Yamashita, Taiga Miyazaki, Yoshiko Fukuda, Junichi Mitsuyama, Tomomi Saijo, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae Citation: Antimicrobial Agents and Chemotherapy, 63(8), e00374-19; 2019 ...