FR901469, a novel antifungal antibiotic from an unidentified fungus No. 11243. III. Structure determination

A novel antifungal antibiotic, FR901469, was isolated from an unidentified fungus No. 11243. It is a water-soluble 40-membered macrocyclic lipopeptidolactone, consisting of D-Ala, L-Tyr, L-Val, trans-4OH-L-Pro, trans-3OH-L-Pro, threo-3OH-L-Gln, Gly, L-Orn, L-Thr, three residues of D-alloThr and a (3R)-hydroxypalmitic acid. Its structure, including absolute configurations, was unequivocally determined as 1 based on chemical and spectroscopic evidence.     

FR901469, a novel antifungal antibiotic from an unidentified fungus No.11243. II. In vitro and in vivo activities

FR901469 is a water-soluble macrocyclic lipopeptidolactone (C71H116N14O23) that has inhibitory activity against 1,3-beta-glucan synthase and exhibits in vitro and in vivo antifungal activity against both Candida albicans and Aspergillus fumigatus. The MICs of FR901469 against Candida albicans FP633 and Aspergillus fumigatus FP1305 in a micro-broth dilution test were 0.63 and 0.16 microg/ml, respectively. FR901469 showed excellent efficacy by subcutaneous injection against both Candida albicans and Aspergillus fumigatus in a murine systemic infection mode, with ED50s of 0.32 and 0.2 mg/kg, respectively. This compound also showed potent anti-Pneumocystis activity in the nude mice model with experimental Pneumocystis pneumonia. The hemolytic activity of FR901469 towards mouse red blood cells, is about 30-fold weaker than that of amphotericin B.     

FR227244, a novel antifungal antibiotic from Myrothecium cinctum No. 002 Taxonomy, fermentation, isolation and physico-chemical properties

A novel antifungal antibiotic, FR227244, was isolated from the culture broth of a fungal strain No. 002. The strain was identified as Myrothecium cinctum from morphological and physiological characteristics. This compound was isolated from the culture broth by solvent extraction, HP-20 and YMC ODS gel column chromatographies, and n-hexane precipitation. FR227244 is a white powder which melts at 210 to approximately 211 degrees C and possesses the molecular formula C38H58O11. FR227244 is a novel triterpene glycoside with antifungal activity against Aspergillus fumigatus. The effects of FR227244 on the morphology of A. fumigatus were shown to be similar to those of FR901379 which is a known 1,3-beta-glucan synthase inhibitor.     

FR109615, a new antifungal antibiotic from Streptomyces setonii. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity

FR109615, a new antibiotic active against Candida, was isolated from Streptomyces setonii No. 7562. Based on the spectroscopic data, the structure of FR109615 was elucidated as cis-2-aminocyclopentane-1-carboxylic acid (1). The compound showed the excellent in vivo efficacy in a generalized infection test of mice.     

FR191512, a novel anti-influenza agent isolated from a fungus strain No.17415. I. Taxonomy, fermentation, isolation, physico-chemical properties and structure elucidation

In the course of our screening for anti-influenza agents of microbial origin, FR191512 was isolated from the cultured broth of fungus strain No. 17415 as colorless powder. The structure of FR191512 was determined by several spectroscopic experiments as a novel polyphenolic compound. This compound showed potent antiviral activity against influenza A virus.     

FR209602 and related compounds, novel antifungal lipopeptides from Coleophoma crateriformis no.738. I. Taxonomy, fermentation, isolation and physico-chemical properties

Novel antifungal lipopeptides, FR209602, FR209603 and FR209604, were isolated from the fermentation broth of a fungal strain No. 738 which was identified as Coleophoma crateriformis from morphological and physiological characteristics. The antibiotics were purified by solvent extraction, HP-20, YMC-ODS and silica gel column chromatography and lyophilization. These compounds were structurally similar to FR901379 previously reported by ourselves which had a sulfate residue in the cyclic peptide portion.     

FR112123, a new oligopeptide antibiotic from Streptomyces viridochromogenes. Taxonomy, fermentation, isolation, physico-chemical properties, structure and biological activity

FR112123 is a new oligopeptide antibiotic produced by Streptomyces viridochromogenes No. 7587. The structure of FR112123 is elucidated as N-(N6-(N2-glycyl-L-glutaminyl)-D-lysyl)-D-alanine (1) by spectroscopic and chemical evidence. It resembles a partial structure of peptidoglycan in bacteria. The compound has a superior activity against an Escherichia coli mutant sensitive to inhibitors of cell wall synthesis, although it has a weak activity against the parent strain. These suggest that FR112123 might act on the biosynthesis of bacterial cell wall.     

Karnamicin, a complex of new antifungal antibiotics. I. Taxonomy, fermentation, isolation and physico-chemical and biological properties

A complex of new antifungal antibiotics designated karnamicin was isolated from the cultured broth of Saccharothrix aerocolonigenes No. N806-4. Fifteen components have so far been isolated from the complex; the major component karnamicin B2 was identified by X-ray crystallography to be a novel molecule unrelated to known antibiotics. All components of karnamicin exhibited a rather broad spectrum of activity against fungi and yeasts with MICs ranging from 3.1 to 50 micrograms/ml.     

A new antimitotic substance, FR182877. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities

Using the characteristic morphological changes of mammalian cells, we screened novel antimitotic substances and found that a strain of Streptomyces sp. No.9885 produced FR182877. This substance was isolated from the culture broth by ethyl acetate extraction, silica gel column chromatography and ODS column chromatography. Structural studies on FR182877 suggested that it had a unique hexacyclic structure encompassing its highly strained double bond. FR182877 exhibited potent antitumor activities against murine ascitic tumor and solid tumor in vivo.     

A novel antibiotic, sohbumycin. Taxonomy, fermentation, isolation and physico-chemical and biological characteristics

A new antibiotic sohbumycin, was isolated from the culture broth of Streptomyces sp. No. 82-85. It appeared to belong to the peptide lactone type of antibiotics from physico-chemical studies and has an empirical formula of C31H47N8O10Cl. In in vitro studies, the antibiotic was found to possess potent cytocidal activity against HeLa S3 cells and antimicrobial activities against Gram-positive bacteria with MIC values about 0.3-0.6 microgram/ml, but showed no activity on the Gram-negative bacteria, yeast and fungi tested.     

FR171456, a novel cholesterol synthesis inhibitor produced by Sporormiella minima No. 15604. I. Taxonomy, fermentation, isolation, physico-chemical properties

FR171456 and FR173945, novel and potent cholesterol synthesis inhibitors, have been isolated from the fermentation broth of a fungal strain No. 15604. This strain was identified Sporormiella minima from its mycological characteristics. FR171456 and FR173945 strongly inhibited cholesterol synthesis in human hepatoma cell line Hep G2. These compounds also have in vitro antifungal activity against Candida albicans and Aspergillus fumigatus.     

Arugomycin, a new anthracycline antibiotic. I. Taxonomy, fermentation, isolation and physico-chemical properties

Arugomycin (AGM) is a new anthracycline antibiotic produced by strain No. 1098-AV2 which was identified as Streptomyces violaceochromogenes. AGM was isolated by solvent extraction, silicic acid chromatography and Sephadex LH-20 column chromatography. Acid treatment of AGM gave the chromophore, named arugorol, which was identified as 4'-epi-nogalarol, and sugar moieties. AGM inhibited the growth of Gram-positive bacteria and showed antitumor activity against sarcoma S-180 and Ehrlich ascites tumors.     

FR252921, a novel immunosuppressive agent isolated from Pseudomonas fluorescens no. 408813. I. Taxonomy,fermentation, isolation,physico-chemical properties and biological activities of FR252921, FR252922 and FR256523

Novel immunosuppressive agents, FR252921, FR252922 and FR256523 were isolated from the cultured broth of a bacterial strain No. 408813. The strain was identified Pseudomonas fluorescens from morphological and physiological characteristics. FR252921, FR252922 and FR256523, novel compounds containing macrolactone ring, showed immunosuppressive activity against murine splenocyte proliferation stimulated with lipopolysaccharide (LPS) or anti-CD3 mAb in vitro.     

A novel antifungal antibiotic, FR-900848. I. Production, isolation, physico-chemical and biological properties

Streptoverticillium fervens produced a new antibiotic, FR-900848, which has a high specific activity against filamentous fungi. Purified by solvent extraction and column chromatography, the compound appears as colorless crystals. Its structure is C32H43N3O6, which consists of 5'-amino-5'-deoxy-5,6-dihydrouridine with an unsaturated fatty acid having unprecedented four serial and one isolated cyclopropane rings.     

FR901512, a novel HMG-CoA reductase inhibitor produced by an agonomycetous fungus No. 14919. II. Taxonomy of the producing organism, fermentation, isolation and physico-chemical properties

Novel compounds FR901512 and FR901516 were isolated from the fermentation broth of agonomycete strain No. 14919. FR901512 and FR901516 possess unique tetralin ring in their structure. These compounds were potent inhibitors of the cholesterol synthesis in human hepatoma cell line Hep G2. FR901512 shows strong 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitory activity with an IC50 value of 0.95 nM.     

Aranorosin, a novel antibiotic from Pseudoarachniotus roseus. I. Taxonomy, fermentation, isolation, chemical and biological properties

A novel antibiotic, aranorosin, was isolated from the fermentation broth of a new fungal isolate identified as Pseudoarachniotus roseus. The antibiotic showed a wide spectrum of activity.     

Leualacin, a novel calcium blocker from Hapsidospora irregularis. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties.

A new calcium blocker, designated leualacin, has been isolated from Hapsidospora irregularis. The compound inhibits the binding of 3H-nitrendipine, a well known synthetic calcium blocker, to cardiac Ca channel in a competitive manner, although its structure is completely different from dihydropyridines.     

FR177391, a new anti-hyperlipidemic agent from Serratia. I. Taxonomy, fermentation, isolation, physico-chemical properties, structure elucidation and biological activities

In the course of screening for a new anti-hyperlipidemic agent from microbial products, we found that FR177391, produced by Serratia liquefaciens No. 1821, alleviated the decrease in lipid droplet formation in differentiated 3T3-L1 adipocyte cells, induced by the addition of tumor necrosis factor-alpha. Structural elucidation by spectroscopic methods and X-ray crystallographic analysis of its propylamide derivative revealed that FR177391 was a chlorinated macrocyclic lactone.     

Novel antifungal antibiotics octacosamicins A and B. I. Taxonomy, fermentation and isolation, physico-chemical properties and biological activities

Two antifungal antibiotics octacosamicins A and B were isolated from the culture broth of a strain of actinomycetes, which was identified as a strain of Amycolatopsis. These antibiotics were isolated by resin adsorption and purified by column chromatography and preparative HPLC. Both antibiotics were found to be new substances from their physico-chemical properties. They showed broad antifungal spectra.     

FR258900, a novel glycogen phosphorylase inhibitor isolated from Fungus No. 138354. I. Taxonomy, fermentation, isolation and biological activities

FR258900 is a novel glycogen synthesis activator produced by Fungus No. 138354. This compound was isolated from the culture broth by solvent extraction and reverse-phase column chromatography. FR258900 stimulated glycogen synthesis and glycogen synthase activity in primary rat hepatocytes. FR258900 exhibited a potent inhibitory effect on the activity of liver glycogen phosphorylase, suggesting that this compound may activate hepatic glycogen synthesis via glycogen phosphorylase inhibition. Thus, this glycogen phosphorylase inhibitor may be useful in the treatment of postprandial hyperglycemia in type 2 diabetes.