title: Simplifungin and Valsafungins, Antifungal Antibiotics of Fungal Origin.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishijima
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Uchida
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ohtawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Ariko
authors.initials: A
authors.lastname: Kondo
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Life Science Business Department, Shimadzu Corporation , Kyoto 604-8511, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shima
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nonaka
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Rokuro
authors.initials: R
authors.lastname: Masuma
authors.affiliation: Chemical Research Laboratories, R&D Division, Kyowa Hakko Kirin Co., Ltd. , 1188 Shimotogari, Nagaizumi-cho, Shizuoka 411-8731, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Iwamoto
authors.affiliation: Chemical Research Laboratories, R&D Division, Kyowa Hakko Kirin Co., Ltd. , 1188 Shimotogari, Nagaizumi-cho, Shizuoka 411-8731, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Onodera
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Nagamitsu
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D002853:Chromatography, Liquid; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry* / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects / Q000254:growth & development; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry
chemical_list: D000935:Antifungal Agents; D005229:Fatty Acids, Monounsaturated; C000627253:simplifungin; C000627257:valsafungin