Search

FR-111142 is a new angiogenesis inhibitor produced by a fungus Scolecobasidium arenarium F-2015. FR-111142 inhibited endothelial cell proliferation in vitro and angiogenesis in the growing chick chorioallantoic membrane model in vivo. Further, FR-111142 also suppressed the solid tumor growth in mice.

WS9326A binds competitively to [3H]substance P (NK-1 receptor) binding sites on guinea-pig lung membranes (IC50 = 3.6 x 10(-6) M), and acts as a tachykinin antagonist in various functional assays. WS9326A inhibited tracheal constrictions produced by exogenously added substance P and neurokinin A, with IC50 values of 9.7 x 10(-6) M and 3.5 x 10(-6) M, respectively. WS9326A inhibited neurokinin A-induced bronchoconstriction in a dose dependent manner when administered to guinea-pigs intravenously together with neurokinin A, and was also effective in preventing capsaicin-induced bronchoconstriction, which is known to be caused by release of endogenous tachykinins (substance P and neurokinin A). FK224 (tetrahydro-WS9326A; catalytic hydrogenation of WS9326A gave FK224) was more potent than WS9326A in the [3H]substance P receptor binding assay using guinea-pig lung membrane (IC50 = 1.0 x 10(-7) M).

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.

Data from several studies suggest that tachykinins may play an important role in the pathophysiology of airway diseases, especially asthma. Our aim is to discover tachykinin antagonists which exhibit therapeutically useful anti-asthmatic activity. In our search for activities inhibiting the binding of [3H]substance P to guinea-pig lung membrane preparations, we have found that the fermentation product, WS9326A, isolated from Streptomyces violaceusniger, is a potent tachykinin receptor antagonist.

WS1358A1, a novel inhibitor of renal dehydropeptidase (DHP), augmented the urinary recovery of a carbapenem antibiotic imipenem and improved its protective effect in experimental infections when simultaneously administered to mice with the antibiotic. WS1358A1 was a competitive DHP inhibitor with a Ki value of 1.6 x 10(-7) M.

WSl358Al (FR104007) and Bl (FR104008), new potent inhibitors of renal dehydropeptidase, were isolated from the culture broth of strain No. 1358 which was identified as Streptomyces parvulus subsp. In vitro inhibitory activities (IC50 value) of WSl358Al and Bl against porcine renal DHP were 3 and 600 nM, respectively.

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.

A new species of Streptomyces is described and designated Streptomyces auranticolor (FERM-P No. 5365) which produces new anticoccidial antibiotics, designated as WS-5995 A and WS-5995 B. The organism is characterized by gray spore mass color, spiral spore chain with smooth spores, non-chromogenic reaction, soluble pigment, and carbon utilization characteristics. It differs from previously described streptomycetes on the basis of carbon utilization, and pigment production.

FR-900109 is a new antibiotic obtained from fermentation broth of a streptomyces which was identified as Streptomyces prunicolor. Its elementary analysis and mass spectroscopic measurement suggest that the molecular formula is C27H32O9. It has an ultraviolet absorption maximum at 254 nm. The antibiotic is active against Gram-positive bacteria. Acute toxicity in mice is very low.

A new subspecies of the genus Streptomyces, for which the name S. libani subsp. rubropurpureus subsp. nov. is proposed, is described. Soil isolate, strain No. 6362, produces a new antitumor substance chromoxymycin. The strain has a gray or red spore mass color, spiral spore chains with smooth spores, is nonchromogenic, and utilizes most carbon sources. Strain No. 6362 is most closely related to S. libani, although there are differences in colorization of reverse colony and spore chain morphology between each other. Those differences are not enough to establish a new species. It is suitable to consider that strain No. 6362 is identified as a new subspecies in the species of S. libani.

A new antitumor antibiotic, WF-3405 was isolated from the culture of Amauroascus aureus F-3405. The structure has been determined as 1, 5-dioxiranyl-1, 2, 3, 4, 5-pentanepentanol on the basis of spectroscopic and chemical evidence. WF-3405 exhibits strong inhibitory activity against various murine tumors including leukemia P388, leukemia L1210 and Lewis lung carcinoma.

An interesting immunoactive peptide, FK-156, has been isolated from the fermentation broth of Streptomyces olivaceogriseus sp. nov. and Streptomyces violaceus. The compound was purified by column chromatography with activated carbon, ion exchange Sephadex and cellulose powder. FK-156, obtained as white powder, exhibits a wide variety of immunostimulatory activity in vivo and in vitro with experimental animals. Pretreatment of mice or rats with this peptide protected the animals against lethal infection with Escherichia coli and resulted in prolongation of life span of tumor bearing animals.

FR-900494 is a new type of immunoactive substances produced by an actinomycete named Kitasatosporia kifunense sp. nov. FR-900494 exhibits a competitive action against immunosuppressive factor produced in the serum of tumor bearing mice and has the capacity to restore the depression of lymphocytes.

The structures of biphenomycins A and B, novel peptide antibiotics produced by a strain of Streptomyces, have been established as 1 and 2, respectively, on the basis of spectroscopic and chemical evidence. They are unique in that they are cyclic peptides containing a biphenyl moiety included in a 15-membered ring and show potent antibacterial activities especially against Gram-positive bacteria.

The structure of FR-900137, a new antibiotic produced by a new strain of Streptomyces has been established as methyl hydrogen N1-methyl N2-(L)-leucyl phosphorohydrazidate on the basis of spectroscopic and chemical evidence.

WB-3559 A, B, C and D were produced by a bacterium which was classified as a member of the genus Flavobacterium. These compounds were purified by solvent extraction followed by chromatography on silica gel and then isolated by HPLC. The chemical structures were determined on the basis of chemical and spectroscopic evidence as in the succeeding papers. WB-3559 A, B, C and D stimulated rabbit plasma euglobulin clot lysis time. A chemically synthesized compound (WB-3559 D-syn) stimulated mouse plasma euglobulin clot lysis time when injected intravenously.

Nocardicin A is a new monocyclic beta-lactam antibiotic obtained from the fermentation broth of a strain of actinomycetes. The producing organism, strain WS 1571, was identified as Nocardia uniformis subsp. tsuyamanensis ATCC 21806. The antibiotic, obtained as colorless crystals, exhibits moderate in vitro antibacterial activity against a broad-spectrum of Gram-negative bacteria including Proteus and Pseudomonas. It has low toxicity in laboratory animals.

A complex of the new antitumor antibiotics (WF-1360, WF-1360A, B, C, D, E and F) was produced by Rhizopus sp. No. F-1360. Structural studies of these compounds suggested that they were novel 16-membered-ring lactones having an oxazole ring in their structures. WF-1360 was found to be identical with rhizoxin (1) and WF-1360B, C, E and F were de-termined to be homologues of 1 with structures 2, 3, 4 and 5, respectively. These compounds were cytotoxic when tested on P388 leukemia cells in vitro. WF-1360 was highly active against leukemia L1210 and melanoma B16. They also exhibited potent antifungal activities, but weak antimicrobial activities against some Gram-positive or negative bacteria.

Lavendomycin, a new basic peptide antibiotic containing novel amino acids, has been isolated from the culture broth of a streptomyces designated as Streptomyces lavendulae subsp. brasilicus. The antibiotic obtained as colorless crystals (C29H50N10O8, MW 666) is active against Gram-positive bacteria in vitro and in vivo, however, inactive against Gram-negative bacteria and fungi. An acute toxicity of the antibiotic in mice was LD50 greater than 2 g/kg by subcutaneous injection.

The structures of WB-3559 A, B, C and D, new fibrinolytic agents isolated from Flavobacterium sp. No. 3559, have been elucidated to be as shown in 1, 2, 3 and 4, respectively, on the basis of chemical and spectroscopic evidence. Total synthesis of WB-3559 D (4) was achieved starting from the optically active aldehyde 14.

Swainsonine isolated from Metarhizium sp., was found to enhance the activities of the mouse immune system in vitro. Concanavalin A stimulated lymphocyte proliferation and proliferative response in mixed lymphocytes culture, which were suppressed by immunosuppressive factor obtained from serum of sarcoma 180 tumor bearing mouse, were restored to normal levels by the addition of swainsonine. Furthermore, the concanavalin A induced incorporation of [3H] thymidine into mouse spleen cells was remarkably increased by treatment with swainsonine over a wide dose range. From studies using fluorescence activated cell sorting, swainsonine was shown to enhance the expression of concanavalin A receptors of spleen cells.

New vasodilators, designated WS-1228 A and B have been discovered in the culture filtrate of a strain of Streptomyces aureofaciens. The active compounds were purified by column chromatography with Diaion HP-20 and silica gel, and finally separated from each other by high performance liquid chromatography. They were obtained as pale yellow crystals and their molecular formulae were both C11H17N3O.

FK409, a novel vasodilator with anti-platelet aggregation activity, has been isolated from the acid-treated fermentation broth of Streptomyces griseosporeus No. 16917, which was cultured on a medium containing NaNO3 for 4 days. FK409 was purified from the culture-filtrate by extraction with ethyl acetate after adjusting the pH to 3.0 with HC1, followed by silica gel chromatography. The molecular formula of this compound was determined to be C8H13N3O4. In vitro, FK409 showed a potent relaxation activity on noradrenaline induced contraction of rat aorta. In addition to the vasodilating activity, this compound also showed potent anti-aggregation activities towards rabbit platelets. In vivo, intravenously administered FK409 resulted in marked blood pressure lowering in rats.

Microscopic examination of cultures of Escherichia coli exposed to bicyclomycin revelaed elongated or spheroplast-like cells. At the lethal level, bicyclomycin was shown to inhibit the synthesis of RNA and protein in the growing cells of E. coli 15 THU, whereas DNA and lipid synthesis were not significantly affected. However, the antibiotic did not block RNA and protein synthesis in vitro. Bicyclomycin was observed to inhibit the synthesis of envelope proteins more markedly than that of cytoplasmic proteins. The synthesis of two major envelope proteins was more sensetive to bicyclomycin than that of the other envelope proteins. One (peak I), which was inhibited to the greatest extent, seemed to be identical with a bound form of lipoprotein, and the other (peak V) with a free form of lipoprotein. Bicyclomycin exhibited inhibitory effects on the exclusive biosynthesis of the lipoprotein in histidine-starved cells of E. coli 15 THU. The biosynthesis of the bound form of lipoprotein was more profoundly inhibited by bicyclomycin than that of the free form. These results indicate that the primary action of bicyclomycin may be due to the interference with the biosynthesis of lipoprotein, and its assembly to peptidoglycan.

A novel antifungal antibiotic, chryscandin was found in the culture broth of a strain of fungi. The producing organism was subsequently identified as Chrysosporium pannorum. The antibiotic obtained as colorless needle crystals (C20H23N7O6, MW 457) is active against Candida albicans and Gram-positive bacteria, but it is ineffective against filamentous fungi and Gram-negative bacteria. Acute toxicity is very low in mice.

The structure of novel phosphonic acid antibiotics, FR-33289, FR-31564, and FR-32863, produced by strains of Streptomyces, have been established as I, II, and III, respectively, on the basis of spectroscopic and chemical evidences.

FR-900130 is a new antibiotic having an acetylene moiety and is very unstable in aqueous solution. The antibiotic was isolated as the acetyl derivative by ion-exchange resin and adsorption chromatography. The structure has been determined to be L-2-amino-3-butynoic acid by spectral data of its derivatives.

The new antitumor antibiotics, FR-900405 and FR-900406, were isolated from the culture broth of Actinomadura pulveracea sp. nov. No. 6049. These compounds which contain sulfur in the molecule, represent a novel class of antitumor agents. FR-900405 and FR-900406 are highly active in mice against experimental tumors and exhibit antimicrobial activity against Gram-positive and Gram-negative bacteria and fungi.

Biphenomycin A, C23H28N4O8, and biphenomycin B, C23H28N4O7, were isolated from the cultured broth of Streptomyces griseorubiginosus No. 43708. The antibiotics are active in vitro and in vivo against bacteria, and are especially potent against Gram-positive bacteria. The acute toxicity of biphenomycin A is very low in mice.

The microbiological characteristics of Streptomyces strain No. 7906 include formation of white aerial mycelium, light brown growth and thick aerial hyphae forming tufts. Strain No. 7906 was compared with known species and identified as a new species and given the name Streptomyces tateyamensis. Streptomyces tateyamensis No. 7906 produces new sulfur-containing peptide antibiotics which are named thiopeptins. The major component, thiopeptin B, is obtained as a crystalline powder decomposing at 219-222°C, and exhibiting optical rotation [a]23D -80°(c 1, chloroform). Its elementary analysis suggested the empirical formula C72H90O22N18S6. The ultraviolet absorption maxima (shoulder) were found at 230-250, 295 and 305 mμ. Thiopeptin B showed strong antibacterial activity against Gram-positive bacteria and had no cross resistance with penicillins, aminoglycoside antibiotics, tetracyclines and macrolides. The administration of 500 mg/kg of this antibiotic into mice by intraperitoneal route did not result in any toxic symptom.

Lavendomycin, a new basic peptide antibiotic containing novel amino acids, has been isolated from the culture broth of a streptomyces designated as Streptomyces lavendulae subsp. brasilicus. The antibiotic obtained as colorless crystals (C29H50N10O8, MW 666) is active against Gram-positive bacteria in vitro and in vivo, however, inactive against Gram-negative bacteria and fungi. An acute toxicity of the antibiotic in mice was LD50 greater than 2 g/kg by subcutaneous injection.

Description de la production par fermentation d'une nouvelle penicilline par Aspergillus canolidus. Determination de l'isolement des proprietes biologiques, des proprietes physicochimiques et de la structure de cet antibiotique

Anti-yeast activity with a series of chryscandin derivatives showed that the O-methyl-L-tyrosyl moiety is not always required for activity at the target site. On the other hand, the adenyl-3'-aminoribofuranuronic acid moiety seems to be essential for biological activity. Therefore, the various acyl derivatives on the amino group of the sugar part of the nucleoside were synthesized. 1-(6-Amino-9H-purin-9-yl)-3-(S-benzyl-L-cysteinylamino)- 1,3-dideoxy-beta-D-ribofuranuronic acid (16) showed the highest efficacy among them against Candida albicans. It exhibited sixteen-fold enhanced activity in vitro compared with that of native chryscandin. The in vivo activity of 16 against experimental infection of C. albicans showed the almost same as that of 5-fluorocytosine and a superior to that of ketoconazole.

An actinomycete which was isolated from a soil sample produces new antitumor substances. The morphological and cultural characteristics of the strain resemble those of the genera Streptomyces Waksman and Henrici 1943 and Actinomadura Lechevalier and Lechevalier 1970. Cell wall composition analysis showed that strain No. 6049 contained meso-2, 6-diaminopimelic acid in its cell wall, and madurose in whole-cell sugars. No sporangia, zoospores or fragmentations of vegetative mycelium are observed. From these results, strain No. 6049 is designated as Actinomadura pulveracea sp. nov.

WS-5995 A, B and C are produced by a new strain of Streptomyces designated Streptomyces auranticolor. These antibiotics were purified by solvent extraction followed by chromatography on silica gel and then crystallized. WS-5995 A (C19H12O6, m.p., 289 approximately 291 degrees C) and WS-5995 B (C19H14O6, sublimation at 300 degrees C) protect chickens from infection with Eimeria tenella, a species of coccidia, which produces morbidity or mortality in chickens. WS-5995 C (C19H14O 7, m.p. 288 approximately 290 degrees C), a biologically inactive component, was found to be converted to WS-5995 A on treatment with trifluoroacetic anhydride.

In a purification study of novel vasodilator FK409 from the fermentation broth of Streptomyces griseosporeus, we found the existence of FR-900411, a precursor of FK409 in the broth, suggesting that FK409 was derived from FR-900411 via a chemical reaction. We therefore isolated FR-900411 from the broth. The structure of FK409 and FR-900411 were determined to be 1 and 2 respectively, on the basis of spectroscopic and chemical evidence.

The biosynthesis of bicyclomycin by Streptomyces. rapporonensis was studied using suspensions of washed mycelium. Nicotinamide and Fe2+ were found to be essential cofactors in the biosynthesis. Production of bicyclomycin was enhanced most effectively in the presence of equal moles of L-leucine and L-isoleucine, which in experiments with radioactively labeled compounds were found to be incorporated into bicyclomycin at equivalent rates. These facts strongly suggest that bicyclomycin biosynthesis involves coupling of equal moles of these two amino acids.

A new species of Streptomyces which produces a new cell wall-inhibitory antibiotic, FR-9000981) containing phosphonic acid in its molecule, is named and described. The species name proposed, Streptomyces rubello, nurinus, refers to the aerial mass color. Streptomyces rubellonturinus subsp. indigoferus also produces FR-900098 and the related compound FR-332892). FR-900098 related compounds, FR-32863) and FR-315642) are produced by Streptomvices lavendulae.

Three phosphonic acid antibiotics were found to be produced in the fermentation broths of Streptomyces. FR-31564 and FR-32863 were produced by Streptomyces lavendulae. FR-33289 was produced by a strain of Streptomyces, identified as Streptomyces rubellomurinus subsp. indigoferus. They are distinct from, but resemble FR-900098 which was reported in our preceding paper, in their chemical and biological characteristics.

A strain of Streptomyces, isolated from a soil sample and identified as Streptomyces xanthocidicus, has been found to produce FR-900148, a new antibiotic containing chlorine in its molecule. The antibiotic inhibits both Gram-positive and negative bacteria. However, it is not effective against wild type of Pseudomonas aerguinosa. Its antibacterial action is considered to result from cell wall synthesis inhibition since it causes spheroplast formation from susceptible cells.

A new species in the genus Streptomyces, for which the name Streptomyces sandaensis sp. nov. is proposed, is described. Soil isolate strain No. 6897 (FERM-P 7654), produces a new antitumor substance FR-900482. The strain has a gray to red spore mass color, Rectus Flexibilis to Retinaculum-Apertum spore chain morphology, smooth spores, and is nonchromogenic. Strain No. 6897 is closely related to Streptomyces aburaviensis and Streptomyces nitrosporeus. But, there are many differences in cultural characteristics and in the utilization of carbohydrates.