Studies on the development of novel antifungals targeted to fungal respiration

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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.