Showing papers in "The Journal of Antibiotics in 1998"

Apicularens A and B, new cytostatic macrolides from Chondromyces species (myxobacteria): production, physico-chemical and biological properties.

Abstract: A novel macrolide, apicularen A, was produced by several species of the genus Chondromyces. Initially it was discovered by bioassay-guided RP-HPLC-fractionation of culture extracts of Chondromyces robustus, strain Cm a13. Apicularen A showed no antimicrobial activity, but was highly cytotoxic for cultivated human and animal cells, with IC50 values ranging between 0.1 and 3 ng/ml. A cometabolite of apicularen A, the N-acetylglucosamine glycoside apicularen B, was distinctly less cytotoxic with IC50 values between 0.2 and 1.2 μg/ml, and showed weak activity against a few Gram-positive bacteria. Apicularen A is chemically closely related to the salicylihalamides A and B from the marine sponge Haliclona sp.

Cystothiazoles A and B, new bithiazole-type antibiotics from the myxobacterium Cystobacter fuscus.

Abstract: New bithiazole-type antibiotics, cystothiazoles A (C20H26N2O4S2) and B (C20H26N2O5S2), have been isolated from a culture broth of the myxobacterium, Cystobacter fuscus. The gross structures of these compounds were elucidated by spectroscopic analysis, and their absolute stereochemistry was determined by chemical degradation of cystothiazole A. Cystothiazole A inhibits fungi and human tumor cells, whereas it is inactive against bacteria. The antifungal activity appears to result from the inhibition of submitochondrial NADH oxidation. Although these compounds are structurally related to the known antibiotic myxothiazol, cystothiazole A was more active against fungi and less cytotoxic than myxothiazol.

Cytotoxic Substances Produced by a Fungal Strain from a Sponge: Physico-chemical Properties and Structures

Abstract: Five novel metabolites, trichodenones A-C (1-3), harzialactone A (4) and B (5), have been isolated together with known R-mevalonolactone (6) from the culture broth of a strain of Trichoderma harzianum OUPS-N115 originally separated from the sponge Halichondria okadai. Their structures have been elucidated by spectral evidence. Among them, 1-3 exhibited significant cytotoxicity against cultured P388 cells.

Alnumycin a new naphthoquinone antibiotic produced by an endophytic Streptomyces sp.

Abstract: The culture broth (5 liters) was separated by filtration followed by concentration under reduced pressure (1 l iter) and extraction with ethyl acetate (3×1 liter). After drying over Na2SO4 the organic layer was evaporated under reduced pressure. The residue of 667mg was dissolved in 10ml hexane/isopropanol (7:3) and fracdonated on a silica gel column (Merck Silica gel 60, 0.1~0.063mm, 1.4×15cm) with the same solvent mixture as eluent. The bioactive fractions were determined

Selective inhibition of the bacterial peptidoglycan biosynthesis by the new types of liposidomycins

Abstract: We examined the inhibitory activity against bacterial peptidoglycan biosynthesis, mammalian glycoprotein biosynthesis and growth of BALB/3T3 cells of four different types of liposidomycins which have the structure with or without sulfate and/or 3-methylglutaric acid moieties. Liposidomycins inhibited peptidoglycan biosynthesis about 30∼500 times more effectively than tunicamycin, whereas liposidomycins inhibited mammalian glycoprotein biosynthesis about 30∼300 times less effectively than tunicamycin. When the cytotoxic effect of liposidomycins and tunicamycin on the growth of mammalian cells were compared, liposidomycins did not show toxicity against BALB/3T3 cell at 25 μg/ml, though tunicamycin inhibited cell growth by 50% at 0.05 μg/ml. On the basis of these results, it is concluded that liposidomycins are selective antibiotics showing highly specific inhibition toward bacterial peptidoglycan biosynthesis.

New brominated and halogen-less derivatives and structure-activity relationship of azaphilones inhibiting gp120-CD4 binding

Abstract: Novel brominated and halogen-less azaphilone (oxoisochromane) derivatives, 5-bromoochrephilone and dechloroisochromophilone IV, and known derivatives, dechloroisochromophilone III and isorotiorin, were isolated from the culture broth of a producing organism of isochromophilones I and II (azaphilones inhibiting gp120-CD4 binding), Penicillium multicolor FO-2338, fermented in a medium containing potassium bromide. Nineteen azaphilone-related compounds isolated from the above strain and from other fungi were tested for the inhibition of gp120-CD4 binding and the structure-activity relationship is discussed. Consequently, 5-bromoochrephilone is the strongest inhibitor (IC50, 2.5 microM). A halogen atom at C-5, a proton at C-8 and a diene structure in C-3 side chain of 6-oxoisochromane ring are necessary for gp120-CD4 binding.

Isolation and Structure of an Antimitotic Cyclic Peptide, Ustiloxin F: Chemical Interrelation with a Homologous Peptide, Ustiloxin B

Abstract: Ustiloxin F, a microtubule inhibitor, was isolated as a minor metabolite of Ustilaginoidea virens. The structure was determined from the spectral data and by chemical interrelation to ustiloxin B through reductive removal of the sulfoxide-containing side chain of ustiloxin B to give ustiloxin F. Ustiloxin F inhibited microtubule assembly with an IC50 value of 10.3 μM.

Novel erythromycins from a recombinant Saccharopolyspora erythraea strain NRRL 2338 pIG1. I. Fermentation, isolation and biological activity.

Abstract: In a previous report, a plasmid, pIG1, which contained the loading domain from the Streptomyces avermitilis polyketide synthase (PKS), promoters from Streptomyces coelicolor and the DEBS1-TE truncated PKS from Saccharopolyspora erythraea, was integrated into the S. erythraea chromosome, effectively replacing the natural erythromycin loading domain with the avermectin loading domain. In this paper, we report the feeding of short-chained fatty acids to this recombinant strain, and its parent, NRRL 2338. Both strains incorporated exogenously supplied fatty acids to produce novel, biologically active, C-13 substituted erythromycins.

MJ347-81F4 A & B, novel antibiotics from Amycolatopsis sp.: taxonomic characteristics, fermentation, and antimicrobial activity.

Abstract: Strain MJ347-81F4 has been found to produce two new cyclic thiazolyl peptide antibiotics, components A and B. Taxonomic studies including morphological and physiological characteristics and chemical analysis of whole cells of the producing strain revealed this microorganism to belong to genus Amycolatopsis, and so we designated the strain Amycolatopsis sp. MJ347-81F4. After 10 to 12 days of fermentation, most of the antibacterial activity was present mainly in the mycelial cake and reached its maximum level. In comparison with reference compounds, A as the major component showed excellent in vitro activity against Gram-positive bacteria including highly methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis with MICs in the range of concentration of 0.006∼0.1 μg/ml. The results on the antimicrobial activity against thiazolyl peptide-resistant mutants of Bacillus subtilis NRRL B-558 indicated that the possible molecular target of MJ347-81F4 component A might be the 50S subunits of the ribosome, the inactivation of which would inhibit protein synthesis.

Erinacine E as a kappa opioid receptor agonist and its new analogs from a basidiomycete, Hericium ramosum.

Abstract: A κ opioid receptor binding inhibitor was isolated from the fermentation broth of a basidiomycete, Hericium ramosum CL24240 and identified as erinacine E (1). Three analogs of 1 were produced by fermentation in other media and by microbial biotransformation. Of these compounds, 1 was shown to be the most potent binding inhibitor. Preliminary SAR studies of these compounds indicated that all functional groups and side chains were required for the activity. Compound 1 was a highly-selective binding inhibitor for the κ opioid receptor: 0.8 μM (IC50) for κ, > 200 μM for μ, and > 200 μM for δ opioid receptor. Compound 1 suppressed electrically-stimulated twitch responses of rabbit vas deferens with an ED50 of 14 μM. The suppression was recovered by adding a selective κ opioid receptor antagonist nor-binaltorphimine, indicating that 1 is a κ opioid receptor agonist.

Cloning and heterologous expression of genes from the kinamycin biosynthetic pathway of Streptomyces murayamaensis.

Abstract: The genes for most of the biosynthesis of the kinamycin antibiotics have been cloned and heterologously expressed. Genomic DNA of Streptomyces murayamaensis was partially digested with Mbo I and a library of ∼40 kb fragments in E. coli XL1-BlueMR was prepared using the cosmid vector pOJ446. Hybridization with the act I probe from the actinorhodin polyketide synthase genes identified two clusters of polyketide genes. After transferal of these clusters to S. lividans ZX7, expression of one cluster was established by HPLC with photodiode array detection. Peaks were identified from the kin cluster for dehydrorabelomycin, kinobscurinone, and stealthin C, which are known intermediates in kinamycin biosynthesis. Two shunt metabolites, kinafluorenone and seongomycin were also identified. The structure of the latter was determined from a quantity obtained from large-scale fermentation of one of the clones.

Cell wall active antifungal compounds produced by the marine fungus Hypoxylon oceanicum LL-15G256. II. Isolation and structure determination.

Abstract: Fermentations of the marine fungus Hypoxylon oceanicum (LL-15G256) were found to have potent antifungal activity. Isolation and purification of the antifungal agents provided two classes of compounds, macrocyclic polylactones and the lipodepsipeptides 15G256γ (1), 15G256δ (2) and 15G256e (3). The isolation and structure elucidation of the lipodepsipeptides, all containing D-glutamate, L-serine, and the rare amino acid β-ketotryptohan, are described in this paper.

New quinolone compounds from Pseudonocardia sp. with selective and potent anti-Helicobacter pylori activity: taxonomy of producing strain, fermentation, isolation, structural elucidation and biological activities.

Abstract: Eight novel quinolones with anti-Helicobacter pylori activity were isolated from the actinomycete Pseudonocardia sp. CL38489. The quinolones were very potent against H. pylori with MICs up to 0.1 ng/ml. The quinolones appear to be specific for H. pylori, since they did not show antimicrobial activity when tested against a panel of other microorganisms.

A new anti-MRSA antibiotic complex, WAP-8294A. I. Taxonomy, isolation and biological activities.

Abstract: WAP-8294A, produced by Lysobacter sp., is a complex consisting of water soluble depsipeptide antibiotics. It was further purified by column chromatographies and HPLC, and 19 components were obtained. WAP-8294A2, a major component, and minor components A1, A4, Ax8, Ax9 and Ax13 were active against Gram-positive bacteria, in particular, methicillin-resistant Staphylococcus aureus (MRSA) in vitro. WAP-8294A2 was highly active in vivo in mice against the systemic infection of MRSA.

Novel Glycopeptide Antibiotics: N-Alkylated Derivatives Active Against Vancomycin-Resistant Enterococci

Abstract: LY264826 (A82846B) is a naturally-occurring glycopeptide antibiotic, differing from vancomycin in the stereochemistry of the amino-sugar of the disaccharide function, and the presence of a third sugar attached at the benzylic position of amino acid residue 6. Despite these seemingly subtle differences, LY264826 is approximately 10 times more active than vancomycin against the enterococci. In the pursuit of new antibiotics active against multiresistant Gram-positive organisms, an extensive side chain SAR was developed focusing on the reductive alkylation of LY264826 at the amino function of the disaccharide moiety. A new series of derivatives having varying degrees of structural diversity in the side chain (e.g. varying lengths and degrees of rigidity) was found to have potent activity against vancomycin-resistant enterococci (MIC's < 1.0 μg/ml) as well as activity against staphylococci and streptococci as good or better than vancomycin.

Cycloepoxydon, 1-hydroxy-2-hydroxymethyl-3-pent-1-enylbenzene and 1-hydroxy-2-hydroxymethyl-3-pent-1,3-dienylbenzene, new inhibitors of eukaryotic signal transduction.

Abstract: In a screening for new inhibitors of NF-KB and AP-1 mediated signal transduction pathways in COS-7 cells using secreted alkaline phosphatase (SEAP) as a reporter gene three novel compounds, cycloepoxydon (1), 1-hydroxy-2-hydroxymethyl-3-pent-1-enylbenzene (2) and 1-hydroxymethyl-3-pent-1,3-dienylbenzene (3) were isolated from fermentations of the deuteromycete strain 45-93. Cycloepoxydon inhibits the TPA-induced NF-KB and AP-1 mediated SEAP expression with an IC50 of 1-2 micrograms/ml (4.2-8.4 microns) and 3-5 micrograms/ml (12.6-21 microns) respectively. 1-Hydroxy-2-hydroxymethyl-3-pent-1-enylbenzene (2) inhibits the TPA-induced NF-KB and AP-1 mediated SEAP expression with an IC50 of 7 micrograms/ml (36.4 microns) and 5 micrograms/ml (26 microns). 3 showed only a weak inhibition of the AP-1 and no influence on NF-KB dependent reporter gene expression. In COS-7 and HeLa S3 cells electrophoretic mobility shift assays showed that cycloepoxydon strongly reduced the TPA and TNF- alpha mediated binding of NF-KB to a high affinity consensus sequence which was due to the inhibition of phosphorylation of the protein IKB.

Terprenins, Novel Immunosuppressants Produced by Aspergillus candidus

Abstract: from the fermentation broth of Aspergillus candidus RF-5672 (FERM BP-5882), which was isolated from a soil sample collected on Shodo Island, Kagawa Prefecture, Japan. In this communication, we report the fermentation, isolation, structure elucidation and biological properties of these terprenins. The activities of the terprenins found were evaluated with respect to proliferation of mouse spleen lymphocytes which had been stimulated with concanavalin A (Con

The synthesis and antibacterial activity of two pyoverdin-ampicillin conjugates, entering Pseudomonas aeruginosa via the pyoverdin-mediated iron uptake pathway.

Abstract: Two pyoverdin-ampicillin conjugates were synthesized and their structures were confirmed by mass spectrometry and NMR spectroscopy. In contrast to ampicillin, the conjugates exhibited high antibacterial activity against Pseudomonas aeruginosa ATCC 15692 and ATCC 27853, effective only against the strain which is using the parent pyoverdin for iron uptake. This suggests that the conjugates enter the bacterial cell via the ferripyoverdin uptake pathway. Growth stimulation studies with conjugates hydrolysed at the β-lactam ring of the ampicillin moiety supported this view.

Spirofungin, a new antifungal antibiotic from Streptomyces violaceusniger Tü 4113.

Abstract: A new secondary metabolite was detected in the culture filtrate and extracts of Streptomyces violaceusniger Tu 4113 by HPLC-diode-array and HPLC-electrospray-mass-spectrometry screening. The compound named spirofungin has a polyketide-spiroketal structure and shows various antifungal activities, particularly against yeasts.

Antifungal activities of rapamycin and its derivatives, prolylrapamycin, 32-desmethylrapamycin, and 32-desmethoxyrapamycin.

Abstract: The antifungal agent rapamycin is highly effective in inhibiting growth of yeast and mold strains. This study demonstrates that in liquid medium, rapamycin is more active than its derivatives (prolylrapamycin, 32-desmethylrapamycin, 32-desmethoxyrapamycin) against Candida albicans, Saccharomyces cerevisiae, and Fusarium oxysporum. All the rapamycins were more active than amphotericin B. Although four other molds were not inhibited in liquid medium, they were very sensitive to rapamycin and its derivatives when tested on agar. The latter assay showed that rapamycin is the most active and 32-desmethylrapamycin is more active than prolylrapamycin and 32-desmethoxyrapamycin. The conclusion of this study is that rapamycin is the most active antifungal agent of the compounds examined. The unexpected finding of high activity of rapamycin and its derivatives against filamentous fungi when assayed by the agar diffusion assay suggests that rapamycin or a derivative may hold promise for chemotherapy against pathogenic molds as well as yeasts.

Micacocidin A, B and C, novel antimycoplasma agents from Pseudomonas sp. II. Structure elucidation.

Abstract: Metal-containing novel heterocyclic antibiotics, micacocidin A (1), B (2), and C (3) have been isolated from the culture filtrate of Pseudomonas sp. No. 57-250. The structure and absolute configuration of micacocidin A, an octahedral Zn2+ complex, was determined by X-ray crystallographic analysis. And then, the structures of the two congeners, micacocidin B (Cu2+ complex) and C (Fe3+ complex) were investigated by employing one dimensional and two dimensional homonuclear and heteronuclear NMR spectroscopies and mass spectrometry.

Micacocidin A, B and C, novel antimycoplasma agents from Pseudomonas sp. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.

Abstract: A Gram-negative bacterium was found to produce a new zinc-containing antibiotics, micacocidin A and related compounds containing Cu or Fe, micacocidin B and C, respectively. These antibiotics were isolated by column chromatography on silica gel, and then separated by preparative TLC and HPLC. These new antibiotics exhibited an excellent activity against Mycoplasma species. The producing bacterium was characterized and ascribed to the genus Pseudomonas.

Isolation of SMTP-3, 4, 5 and -6, novel analogs of staplabin, and their effects on plasminogen activation and fibrinolysis.

Abstract: Four novel triprenyl phenol metabolites, designated SMTP-3, -4, -5, and -6, have been isolated from cultures of Stachybotrys microspora IFO 30018 by solvent extraction and successive chromatographic fractionation using silica gel and silica ODS columns. A combination of spectroscopic analyses showed that SMTP-3, -4, -5, and -6 are staplabin analogs, containing a serine, a phenylalanine, a leucine or a tryptophan moiety in respective molecules in place of the N-carboxybutyl portion of the staplabin molecule. SMTP-4, -5, and -6 were active at 0.15∼0.3 mM in enhancing urokinase-catalyzed plasminogen activation and plasminogen binding to fibrin, as well as plasminogen- and urokinase-mediated fibrinolysis. On the other hand, the concentration of staplabin required to exert such effects was 0.4∼0.6 mM, and SMTP-3 was inactive at concentrations up to 0.45 mM.

Antimalarial Activity of Radicicol, Heptelidic Acid and Other Fungal Metabolites

Abstract: In the course of our screening program for artemisinin-like antimalarial compounds from microorganisms, seven fungal metabolites such as radicicol and heptelidic acid were identified as active compounds. Some of them exhibited antimalarial activity in vitro against the human malaria parasite Plasmodium falciparum to the extent of approximately 1/10 as potent as artemisinin. Radicicol was moderately active in vivo against Plasmodium berghei in mice.

Novel lactone compounds from Mortierella verticillata that induce the human low density lipoprotein receptor gene: fermentation, isolation, structural elucidation and biological activities.

Abstract: Among methods of controlling hypercholesterolemia and hyperlipidemia is the direct stimulation of hepatic low density lipoprotein (LDL) receptors. Two novel lactone compounds, CJ-12, 950 and CJ-13, 357, containing an unusual oxime moiety, were isolated from a zygomycete Mortierella verticillata. These lactones are potent inducers of the LDL receptor gene in vitro, that enhanced LDL receptor expression in human hepatocytes 2-fold at 100nM.

Cell wall active antifungal compounds produced by the marine fungus hypoxylon oceanicum LL-15G256. I. Taxonomy and fermentation.

Abstract: The cell wall targeted antifungal activity of Hypoxylon oceanicum LL-15G256 extracts resulted from the production of novel lipodepsipeptides and previously reported macrocyclic polylactones. In an optimized medium, titers of the lipodepsipeptide and the polylactones reached approximately 200-400 mg/liter and 25-50 mg/liter, respectively. The optimum fermentation temperature for production of 15G256γ was 28°C. Seawater appeared to have an inhibitory effect on metabolite accumulation at lower fermentation temperatures.

Isolation and characterisation of an antifungal antibiotic (GR135402) with protein synthesis inhibition.

Abstract: A novel antifungal antibiotic GR135402 has been isolated from a fermentation broth of Graphium putredinis which inhibited protein synthesis in Candida albicans but not rabbit reticulocytes. The spectrum of activity included C. albicans and Cryptococcus neoformans but not some other Candida species or Aspergillus species. Therapeutic efficacy in a mouse model of systemic candidosis was attained following parenteral dosing.

Pulchellalactam: A CD45 Protein Tyrosine Phosphatase Inhibitor from the Marine Fungus Corollospora pulchella

Abstract: CD45 protein tyrosine phosphatase is a largemolecular mass transmembrane glycoprotein expressed on all hematopoietic cells except erythrocytes.1) It is a member of the receptor-like transmembrane protein tyrosine phosphatase2) (PTPase) family. Expression of CD45 has been shown to be important for activation of both B and T cells via their antigen-specific receptors3,4) and has generated considerable interest in the study of lymphocyte activation as well as a possible target for drug intervention in various auto-immune and/or inflammatory diseases. As a part of our effort to find enzyme inhibitors from microbial sources, we identified a fungal extract which exhibited very potent activity in our CD45 assay. Bioassay directed fractionation of the crude extract yielded a novel pulchellalactam (1) as the active component of this extract. Here we describe the isolation, structure determination and biological characteristics of 1. The recombinant baculovirus was constructed to encode the entire cytoplasmic domain of the human CD45 tyrosine phosphatase protein (CD45-IPD), consisting of two tandem PTPase domains. The recombinant protein was produced in a baculovirus expression system using Sf9 insect cells. Furthermore, the vector was designed to produce a fusion protein containing a poly-

K1115 A, a new anthraquinone that inhibits the binding of activator protein-1 (AP-1) to its recognition sites. II. Taxonomy, fermentation, isolation, physico-chemical properties and structure determination.

Abstract: A new inhibitor of the action of activator protein-1 (AP-1), designated K1115 A, was isolated from the fermentation broth of an actinomycete strain Mer-K1115. K1115 A was determined to be a new anthraquinone, 3,8-dihydroxy-1-propylanthraquinone-2-carboxylic acid, based on spectroscopic analysis, derivatization experiments and biosynthetic studies with 13C-enriched acetic acid. Two co-produced compounds, K1115 B1 and B2, were also isolated and characterized as new members of the naphthopyranomycin and exfoliamycin group.