title: AS2077715 is a selective inhibitor of fungal mitochondrial cytochrome bc₁ complex.
abstract: AS2077715 is a novel antifungal metabolite produced by the newly isolated fungal strain Capnodium sp. 339855. This compound has an analogous structure to funiculosin, an inhibitor of mitochondrial cytochrome bc1 complex (complex III). AS2077715 inhibited ubiquinol-cytochrome c reductase activity of Trichophyton mentagrophytes complex III with an IC50 of 0.9 ng ml(-1), while 6000-20,000 ng ml(-1) AS2077715 was required to obtain comparable inhibition of mammalian complex III. This inhibitor also suppressed the growth of T. mentagrophytes with a MIC of 0.08 μg ml(-1), while cytotoxicity for mammalian cells was >6 μg ml(-1). These results indicate that AS2077715 is a selective inhibitor of fungal mitochondrial complex III. AS2077715 in doses of 1 μg ml(-1) or greater showed fungicidal activity against T. mentagrophytes within 2 h of incubation. This early-onset effect of fungicidal activity was also exhibited by other complex III inhibitors. These results suggest that inhibition of complex III is a promising strategy for designing anti-Trichophyton agents and that AS2077715 can be a potential drug candidate for treating Trichophyton infections.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ohsumi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Fujie
mesh_terms: D000935:Antifungal Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001203:Ascomycota / Q000378:metabolism; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D014249:Trichophyton / Q000187:drug effects / Q000254:growth & development
chemical_list: D000935:Antifungal Agents; D001688:Biological Products; D004791:Enzyme Inhibitors; D014450:Electron Transport Complex III