ABSTRACT
During our screening program for new potentiators of amphotericin B activity against Candida albicans, shodoamides A to C (1-3) were isolated from a culture broth of the fungus Pseudophialophora sp. BF-0158 fermented under shaking conditions. A known congener named shodoamide D (4) in this paper was obtained from a culture broth of the BF-0158 strain fermented under static conditions. The structures of 1-4 were assigned based on spectroscopic analyses, including NMR and MS, and were found to have a common N-(2´,3´,4´-trihydroxybutyl)-6-methyl-2,4-tetradecadienamide structure. Compounds 1-3 exhibited no antifungal activity, but they induced up to 32-fold increases in amphotericin B activity against C. albicans by a microdilution method.
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.
Subject(s)
Antifungal Agents/chemistry , Fatty Acids, Monounsaturated/chemistry , Antifungal Agents/pharmacology , Chromatography, Liquid , Fatty Acids, Monounsaturated/pharmacology , Fungi/drug effects , Fungi/growth & development , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Structure , Stereoisomerism , Tandem Mass SpectrometryABSTRACT
The silkworm infection assay is a useful method for directly evaluating the in vivo therapeutic effects of drug candidates. In the present study, 3 known trichothecenes, trichodermin, epiisororidin E, and verrucarin A, were evaluated as antifungal agents in the silkworm-Candida albicans assay. Trichodermin and epiisororidin E yielded effective therapeutic effects, while verrucarin A exhibited no efficacy in this assay system. These results strongly suggest that trichodermin and epiisororidin E are the lead compounds for developing a new antifungal agent.
Subject(s)
Antifungal Agents/pharmacology , Bombyx/drug effects , Candida albicans/drug effects , Candidiasis/drug therapy , Drug Discovery/methods , Trichothecenes/pharmacology , Animals , Antifungal Agents/toxicity , Bombyx/embryology , Bombyx/microbiology , CHO Cells , Candida albicans/pathogenicity , Candidiasis/microbiology , Cell Survival/drug effects , Cricetulus , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Larva/drug effects , Larva/microbiology , Trichodermin/pharmacology , Trichothecenes/toxicityABSTRACT
A new antioxidant, designated pyranonigrin L, was isolated from the culture materials of the hot spring-derived fungus Penicillium adainetzii BF0003 by solvent extraction, ODS column chromatography, and HPLC. Its planar structure was elucidated using various analytical techniques including UV, IR, and NMR spectroscopy and MS. Its absolute configuration was determined by a comparison of its circular dichroism (CD) spectrum with those of structurally related compounds. Pyranonigrin L was found to exhibit anti-oxidative activity with an EC(500 value of 553 µM.
