Studies on the development of novel antifungals targeted to fungal respiration

目前，迫切需要具有新靶点和作用机制的新型抗真菌药物。我已经观察到了高度特异的呼吸抑制物在体外对病原真菌的生长抑制作用，它抑制了真菌线粒体的电子传递，在能量代谢中起着关键作用。本研究详细考察了候选化合物对致病酵母菌的作用，为以线粒体呼吸系统为靶点的抗真菌药物的临床应用奠定了基础。利用麦芽假丝酵母菌核编码交替氧化酶基因突变株的能量代谢和氧化应激损伤来阐明交替氧化酶的生理作用和阿司可呋喃酮的抑制机制。从我的研究背景来看，通过联合使用抑制氰化物敏感呼吸的阿托瓦酮和抑制抗氰化物呼吸的阿斯可呋酮所获得的体外结果被认为与整体动物体内实验密切相关。因此，我们在临床常用抗真菌药物(氮唑类、两性霉素B、米卡芬净等)存在或不存在的情况下，对阿托瓦酮和阿舒呋喃酮对白念珠菌体外生长的影响进行了全面的研究，以证实其临床疗效。

Presently, there is a pressing need for novel antifungals possessing novel targets and action mechanisms. I already observed the in vitro potent growth inhibition of pathogenic fungi by the highly specific respiratory inhibitors which inhibit the fungal mitochondrial electron transport playing a key role in the energy metabolism. In this study, effects of the candidates on the pathogenic yeasts were examined in detail to establish the basis for the clinical application of the antifungals targeted to the mitochondrial respiratory system.The energy metabolism and oxidative stress damage of the nuclear-encoded alternative oxidase gene disrupted mutants of Candida maltosa were used to elucidate the physiological role of alternative oxidase and the inhibitory mechanism of ascofuranone.From my research background, in vitro results obtained by the combined addition of atovaquone, which inhibits cyanide-sensitive respiration, and ascofuranone, which inhibits cyanide-resistant respiration, are thought to be closely related to in vivo experiments using whole animals. Accordingly, effects of atovaquone and asucofuranone on the in vitro cell growth of Candida albicans have been examined comprehensively in the presence or absence of clinically used antifungals (azoles, amphotericin B, micafungin etc.), in order to confirm the clinical efficacy.