Pleofungins, novel inositol phosphorylceramide synthase inhibitors, from Phoma sp. SANK 13899. II. Structural elucidation

Pleofungins (formerly called F-15078) A, B, C and D, novel depsipeptide antifungal antibiotics, were found in a mycelium extract of the producing fungus, Phoma sp. SANK 13899. The structures of pleofungins A, B, C and D were elucidated mainly by various NMR studies. The absolute configurations of the amino acids and N-methyl amino acids of pleofungin A constituents in the hydrolysate were determined by the application of advanced Marfey's method in combination with gas chromatography/mass spectrometry analysis of their silylation products with N-methyl-N-(tert-butylsilyl)trifluoroacetamide. Two alpha-hydroxy acid constituents, alpha-hydroxyisocaproic acid and alpha-hydroxyisovaleric acid, were isolated from the hydrolysate and their stereochemistries were determined by their specific rotations.     

Bisabosquals, novel squalene synthase inhibitors. I. Taxonomy, fermentation, isolation and biological activities

In the course of screening for yeast squalene synthase inhibitors, bisabosqual A was isolated from the culture broth of Stachybotrys sp. RF-7260. The related compounds bisabosquals B, C and D were also isolated from Stachybotrys ruwenzoriensis RF-6853. Bisabosquals inhibited squalene synthases. IC50 values of bisabosqual A against the microsomal squalene synthases from Saccharomyces cerevisiae, Candida albicans, HepG2 cell and rat liver were 0.43, 0.25, 0.95 and 2.5 microg/ml, respectively. Bisabosqual C exhibited inhibitory activities similar to bisabosqual A. Bisabosqual A showed broad spectrum antifungal activity in vitro.     

The squalestatins, novel inhibitors of squalene synthase produced by a species of Phoma. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity.

During the screening of fungi for inhibitors of squalene synthase, Phoma sp. C2932 was found to produce three structurally related novel inhibitors. These compounds, designated the squalestatins, exhibited potent activity against both mammalian (rat liver) and fungal (Candida albicans) squalene synthase. Furthermore, they also had broad spectrum in vitro antifungal activity.     

ICM0301s, new angiogenesis inhibitors from Aspergillus sp. F-1491. I. Taxonomy, fermentation, isolation and biological activities

In the course of screening program for inhibitors of angiogenesis, novel substances designated as ICM0301A approximately H (1 approximately 8) were isolated from the culture broth of Aspergillus sp. F-1491. ICM0301s inhibited the growth of human umbilical vein endothelial cells (HUVECs) induced by basic fibroblast growth factor (bFGF) with IC50 values of 2.2 approximately 9.3 microg/ml. ICM0301A (1) showed significant anti-angiogenic activity at lower than 10 microg/ml in the angiogenesis model using rat aorta cultured in fibrin gel. ICM0301s showed very low cytotoxicity against various tumor cells. Furthermore, 1CM0301A did not show any toxic symptom in mice by intraperitoneal injection at 100 mg/kg.     

New dithiolopyrrolone antibiotics from Saccharothrix sp. SA 233. I. Taxonomy,fermentation, isolation and biological activities

Three new natural antibacterial and antifungal dithiolopyrrolone antibiotics were isolated along with the known iso-butyropyrrothine and thiolutine from the fermentation broth of an actinomycete strain which was isolated from a saharian palm grove soil collected at Adrar, south Algeria. The strain was identified as Saccharothrix sp. The three new antibiotics exhibited broad antimicrobial activity against gram-positive bacteria, yeasts and fungi in vitro.     

SF2809 compounds, novel chymase inhibitors from Dactylosporangium sp. 1. Taxonomy, fermentation, isolation and biological properties

Six novel chymase inhibitors, SF2809-I, SF2809-II, SF2809-III, SF2809-IV, SF2809-V and SF2809-VI, were isolated from the fermentation broth of an actinomycete strain SF2809. The strain was identified as Dactylosporangium sp. by morphological, chemotaxonomical and phylogenetic studies. These six novel compounds inhibited recombinant human chymase in the range between IC50 of 0.014 and 7.3 microM. However, they showed little or no inhibitory activity against chymotrypsin or cathepsin G, even though these two and chymase belong to the chymotryptic serine protease family. This result indicates that these compounds work as specific chymase inhibitors.     

Radamycin,a novel thiopeptide produced by streptomyces sp. RSP9. I. Taxonomy,fermentation, isolation and biological activities

The newly isolated strain Streptomyces sp. RSP9 produces two thiopeptides; one of them is methylsulfomycin I, which shows potent antibiotic activity against several gram-positive bacteria such as Micrococcus luteus and Staphylococcus aureus. The other is a new thiopeptide named radamycin. In the present work, this compound was purified and tested against several microorganisms and no antibiotic activity was detected in the assays. However, it does have a very strong capacity as an inducer of the tipA promoter, and indeed is the first reported molecule with tipA promoter induction capacity without detectable antibiotic activity. Induction of the tipA promoter also occurs with methylsulfomycin I.     

Gerfelin, a novel inhibitor of geranylgeranyl diphosphate synthase from Beauveria felina QN22047. I. Taxonomy, fermentation, isolation, and biological activities

A new compound, gerfelin, was isolated from a culture broth of Beauveria felina QN22047. It was purified by column chromatography on silica gel and by HPLC. Gerfelin has the molecular formula C15H14O6. It inhibited synthesis of geranylgeranyl diphosphate, which was mediated by recombinant human geranylgeranyl diphosphate synthase (hGGPP synthase) in vitro. The inhibitory pattern of gerfelin was noncompetitive against isopentenyl diphosphate, and uncompetitive against farnesyl diphosphate.     

Tripropeptins, novel antimicrobial agents produced by Lysobacter sp. I. Taxonomy, isolation and biological activities

Peptide antibiotics tripropeptins A, B, C, D and Z were isolated from cultured cells and broth of Lysobacter sp. The differences among these components are in the lengths of the alkyl side chain. Tripropeptins are active against Gram-positive bacteria including MRSA in vitro. Bactericidal activity of tripropeptin C disappeared in the simultaneous presence of chloramphenicol, a bacteriostatic agent.     

SW-163C and E, novel antitumor depsipeptides produced by Streptomyces sp. I. Taxonomy, fermentation, isolation and biological activities

Novel depsipeptides, SW-163C and E were isolated from the culture broth of an actinomycete strain. The producing organism, designated as SNA15896, was identified as a member of Streptomyces from its morphological and cultural characteristics. SW-163C and E exhibited potent antitumor activities against various tumor cell lines in vitro and against murine leukemia P388 in vivo. The compounds also showed antimicrobial activities.     

The novel gluconeogenesis inhibitor FR225654 that originates from Phoma sp. no. 00144. I. Taxonomy, fermentation, isolation and physico-chemical properties

FR225654, a novel gluconeogenesis inhibitor, was isolated from the culture broth of Phoma sp. No. 00144 and purified by adsorptive resin and reverse-phase column chromatography. This compound is a potent inhibitor of gluconeogenesis and is a promising candidate of anti-diabetic agent.     

Mutactimycin PR, a new anthracycline antibiotic from Saccharothrix sp. SA 103. I. Taxonomy, fermentation, isolation and biological activities

In the course of screening for new antibacterial agents, a new isolate collected from a soil sample of an arid area in south Algeria, produced a red pigment which was shown an antagonistic action against a gram-positive bacterium Bacillus subtilis. The isolate was identified as Saccharothrix sp. and named SA 103. The red pigment, eluted by HPLC on reverse phase C18 column, contained two compounds of an anthracycline antibiotics group. The structure of the major product (2) was characterized as mutactimycin C, and PR (1) was a new member of this group, designated as mutactimycin PR. These compounds showed an antibiotic activity against certain gram-positive bacteria in vitro. This is the first report of mutactimycins production by the genus Saccharothrix.     

Nocathiacins,new thiazolyl peptide antibiotics from Nocardia sp. I. Taxonomy,fermentation and biological activities

Thiazolyl peptide antibiotics, nocathiacin I, II and III, were identified in a culture of Nocardia sp. WW-12651 (ATCC 202099). They exhibit potent in vitro activity (ng/ml) against a wide spectrum of gram-positive bacteria, including multiple-drug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Enterococcus faecium (MREF) and fully penicillin-resistant Streptococcus pneumoniae (PRSP), and demonstrate excellent in vivo efficacy in a systemic Staphylococcus aureus infection mice model.     

Rhodopeptins (Mer-N1033), novel cyclic tetrapeptides with antifungal activity from Rhodococcus sp. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities

Five novel cyclic tetrapeptides, named rhodopeptin C1, C2, C3, C4 and B5, were isolated from a strain named Rhodococcus sp. Mer-N1033. They are a novel type of cyclic tetrapeptide composed of a beta-amino acid and three usual alpha-amino acids. Rhodopeptins show high in vitro antifungal activity against Candida albicans and Cryptococcus neoformans, whereas they show no activity against bacteria.     

ICM0201, a new inhibitor of osteoclastogenesis from Cunninghamella sp. F-1490. I. Taxonomy,fermentation, isolation and biological activities

In the course of screening for inhibitors of osteoclastogenesis, a new substance designated as ICM0201 was isolated from a fermentation broth of Cunninghamella sp. F-1490. ICM0201 inhibited the formation of osteoclasts in mouse bone marrow cells with an IC50 value of 0.78 microg/ml and showed weak cytotoxicity against bone marrow cells.     

Trierixin, a novel Inhibitor of ER stress-induced XBP1 activation from Streptomyces sp. 1. Taxonomy, fermentation, isolation and biological activities

In the course of screening for an inhibitor of ER stress-induced XBP1 activation, we isolated a new member of the triene-ansamycin group compound, trierixin, from a culture broth of Streptomyces sp. AC 654. Trierixin was purified by column chromatography on silica gel and by HPLC. The molecular formula of trierixin is C(37)H(52)N(2)O(8)S. Trierixin inhibited thapsigargin-induced XBP1-luciferase activation in HeLa/XBP1-luc cells and endogenous XBP1 splicing in HeLa cells with an IC(50) of 14 ng/ml and 19 ng/ml, respectively. Moreover, in the process of isolating trierixin, we isolated structurally related mycotrienin II and trienomycin A as inhibitors of ER stress-induced XBP1 activation from a culture broth of a trierixin-producing strain. This study provides the first observation that triene-ansamycins have a novel inhibitory effect against XBP1 activation.     

TMC-86A, B and TMC-96, new proteasome inhibitors from Streptomyces sp. TC 1084 and Saccharothrix sp. TC 1094. I. Taxonomy, fermentation, isolation, and biological activities

TMC-86A, B and TMC-96, new 20S proteasome inhibitors with an epoxy-beta-aminoketone moiety, were isolated from the fermentation broth of Streptomyces sp. TC 1084 and Saccharothrix sp. TC 1094, respectively. TMC-86A, B and TMC-96 inhibited the chymotrypsin-like and peptidylglutamyl-peptide hydrolyzing activities of 20S proteasome with the following IC50 values: TMC-86A, 5.1 microM and 3.7microM; TMC-86B, 1.1 microM and 31 microM; TMC-96, 2.9 microM and 3.5 microM, respectively. TMC-86A, B and TMC-96 exhibited the weak inhibitory activity against the trypsin-like activity of 20S proteasome with IC50 values of 51 microM, 250 microM, and 36 microM, respectively. They did not inhibit m-calpain, cathepsin L, and trypsin at 100 microM, suggesting their high specificity for proteasome. Taxonomy of the producing strains is also described.     

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.     

Terreulactones A,B, C,and D: novel acetylcholinesterase inhibitors produced by Aspergillus terreus. I. Taxonomy,fermentation, isolation and biological activities

In the course of screening for selective inhibitors of acetylcholinesterase from the microbial metabolites, four new meroterpenoid compounds, terreulactones A, B, C and D were isolated from solid state fermentation of Aspergillus terreus Fb000501. They showed potent inhibitory activities against acetylcholinesterase with IC50 values in range of 0.06 to approximately 0.42 microM. In addition, they exhibited more than 500 to approximately 3000 times selectivity for acetylcholinesterase compared with butyrylcholinesterase.     

Kigamicins, novel antitumor antibiotics. I. Taxonomy, isolation, physico-chemical properties and biological activities

Novel antibiotics named kigamicin A, B, C, D, and E were discovered from the culture broth of Amycolatopsis sp. ML630-mF1 by their selective killing activity against PANC-1 cells only under a nutrient starved condition. Under a condition of nutrient starvation, kigamicins A, B, C, and D inhibited PANC-1 cell survival at 100 times lower concentration than in normal culture. Kigamicins showed antimicrobial activity against Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA). Kigamicin D inhibited the growth of various mouse tumor cell lines at IC50 of about 1 microg/ml.