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.

Sphingolipid biosynthesis in man and microbes

“…FKH-53 respectively. 174 All three compounds inhibited the growth of zygomycetous fungi. Derivatives of simplifungin and valsafungin were almost all less effective antifungals than the parent compounds, with the exception of a methylated derivative of simplifungin, which gave MICs as low as 0.125 μg mL –1 against S. cerevisiae .…”

Antifungal Drug Development: Targeting the Fungal Sphingolipid Pathway

“…Nonetheless, some myriocin derivatives may hold great promise for the treatment of fungal infections. For instance, simplifungin and valsafungins A and B block SPT activity and they do exhibit potent fungicidal activity against C. albicans [ 45 ]. The structure activity relationship of myriocin derivatives led to the discovery of totally new compounds, such as FTY720 and BAF312.…”

Probing key organic substances driving new particle growth initiated by iodine nucleation in coastal atmosphere

“…Nonprotein amino acid C18H37NO4 saturated dihydroxy amino acid (simplifungin, Marine fungal metabolites (Ishijima et al, 2016;VanMiddlesworth et al, 1992). -Erijman et al, 1993) S/N 10-60…”

“…CC BY 4.0 License. (Ishijima et al, 2016;VanMiddlesworth et al, 1992;Jares-Erijman et al, 1993;Tsukamoto et al, 2001). They include saturated dihydroxy amino acid (C18H37NO4, DBE = 1, simplifungin), monounsaturated polyhydroxy amino acids in sphigolipids (C20-22H39-41NO5-7, DBE = 2-3), polyhydroxy amino alcohols (C16-28H33-53N1-2O1-5, DBE = 1-3, sphingosine and its natural metabolites) and polyunsaturated amino alcohols (C18H31NO and C18H29NO, DBE = 4-5).…”