Simplifungin and Valsafungins, Antifungal Antibiotics of Fungal Origin

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• 作者：Hiroyuki Ishijima ; Ryuji Uchida ; Masaki Ohtawa ; Ariko Kondo ; Kenichiro Nagai ; Keisuke Shima ; Kenichi Nonaka ; Rokuro Masuma ; Susumu Iwamoto ; Hideyuki Onodera ; Tohru Nagamitsu ; Hiroshi Tomoda
• 刊名：Journal of Organic Chemistry
• 出版年：2016
• 出版时间：September 2, 2016
• 年：2016
• 卷：81
• 期：17
• 页码：7373-7383
• 全文大小：461K
• 年卷期：0
• ISSN：1520-6904

文摘

The targets of antifungal antibiotics in clinical use are more limited than those of antibacterial antibiotics. Therefore, new antifungal antibiotics with different mechanisms of action are desired. In the course of our screening for antifungal antibiotics of microbial origins, new antifungal antibiotics, simplifungin (1) and valsafungins A (2) and B (3), were isolated from cultures of the fungal strains Simplicillium minatense FKI-4981 and Valsaceae sp. FKH-53, respectively. The structures of 1 to 3 including their absolute stereochemistries were elucidated using various spectral analyses including NMR and collision-induced dissociation (CID)-MS/MS as well as chemical approaches including modifications to the Mosher’s method. They were structurally related to myriocin. They inhibited the growth of yeast-like and zygomycetous fungi with MICs ranging between 0.125 and 8.0 μg/mL. An examination of their mechanisms of action by the newly established assay using LC–MS revealed that 1 and 2 inhibited serine palmitoyltransferase activity, which is involved in sphingolipid biosynthesis, with IC₅₀ values of 224 and 24 nM, respectively.