ABSTRACT
Zaragozic acid A analogues are produced by an unidentified sterile fungus when it is exogenously supplied with 2-thiophenecarboxylic acid, 3-thiophenecarboxylic acid, 2-furoic acid, 2-fluorobenzoic acid, 3-fluorobenzoic acid, or 4-fluorobenzoic acid. The analogues carry 2-thiophenyl, 3-thiophenyl, 2-furyl, o-fluorophenyl, m-fluorophenyl, or p-fluorophenyl group, respectively, at C-6' of the C-1 alkyl side chain replacing the phenyl group of natural zaragozic acid A. All the new analogues of zaragozic acid A possess picomolar inhibitory activity against squalene synthase in vitro.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic , Bridged Bicyclo Compounds/metabolism , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Fungi/metabolism , Tricarboxylic Acids/metabolism , Fungi/drug effects , Magnetic Resonance SpectroscopyABSTRACT
The microbiological transformation of L-696,474 [1], a novel cytochalasin that is an inhibitor of HIV-1 protease, was investigated using Actinoplanes sp. ATCC 53771. Six hydroxylated metabolites 2-7 of 1 were isolated and purified using reversed-phase hplc. All six metabolites were found to have undergone hydroxylation at the C-16 methyl group (C-22) of 1. Three of the compounds, 3, 4, and 5, were further hydroxylated at the para (C-29), the meta (C-28), and both the para and the meta, positions of the phenyl ring, respectively. Metabolites 6 and 7 were shown to result from vicinal dihydroxylation on both C-16 and its attached Me (C-22). The metabolite 7 was further hydroxylated on the meta position of the phenyl ring. The structures of the metabolites were established using spectroscopic techniques including ms, 1H nmr, 13C nmr, and various 2D nmr spectroscopy experiments.
Subject(s)
Actinomycetales/metabolism , Cytochalasins/metabolism , HIV Protease Inhibitors/metabolism , Amino Acid Sequence , Biotransformation , Hydroxylation , Isoindoles , Molecular Sequence DataABSTRACT
We have developed a liquid fermentation medium for the submerged culture of the fungus, Zalerion arboricola, which supports the rapid production of an echinocandin-type antibiotic, pneumocandin A0 (formerly L-671,329), in yields increased at least 4-fold over those reported previously. The improvements were achieved through medium simplification, substitution of high levels of mannitol for glycerol as the major source of carbon, and restriction of available magnesium. Antibiotic formation in batch cultures with this mannitol-based medium is not confined to the idiophase; rather production appears to be biphasic, with synthesis beginning during growth (i.e., at day 3) and increasing in rate at day 11, well after rapid growth has ended. Accumulation of antibiotic continues beyond 14 days, and by 21 days titers greater than 500 micrograms/ml are attained. For the synthesis of a related compound, pneumocandin B0, by a mutant strain of Z. arboricola, the medium gives similar production kinetics and a titer of 800 micrograms/ml. Although supplementation of the medium with magnesium ions stimulates growth, it decreases titer by preferentially affecting the second phase of antibiotic synthesis. This decline in synthesis in the magnesium-supplemented medium is explained by the depletion of mannitol before the second phase of synthesis can begin. In contrast, mannitol in the magnesium-limited medium is used more slowly with approximately half still available at day 11 to support continued antibiotic formation.
Subject(s)
Anti-Bacterial Agents , Antifungal Agents/biosynthesis , Culture Media/chemistry , Magnesium/pharmacology , Mannitol/pharmacology , Mitosporic Fungi/metabolism , Peptides , Echinocandins , Fermentation , Mitosporic Fungi/drug effects , Mitosporic Fungi/growth & development , Peptides, Cyclic/biosynthesisABSTRACT
The microbial metabolism of MK 954 (Fig. 1), a novel nonpeptide angiotensin II receptor antagonist, was investigated using 40 microorganisms in an initial screen for cultures that will produce metabolites similar to those produced in the mammalian liver. The microbial transformation occurred under aerobic conditions in shake flasks incubated at 27 degrees C. Three metabolites of MK 954 were isolated and identified as the 1'-hydroxy M2, 3'-hydroxy M1, and glucuronic acid conjugated M3 derivatives. The structures of the metabolites were established by UV, 1H-NMR spectroscopy and FAB-MS spectrometry and are identical to metabolites produced by incubation of MK 954 with mammalian liver slices.
Subject(s)
Actinomycetales/metabolism , Angiotensin II/antagonists & inhibitors , Biphenyl Compounds/metabolism , Glucuronates/metabolism , Imidazoles/metabolism , Receptors, Angiotensin/drug effects , Streptococcus/metabolism , Tetrazoles/metabolism , Angiotensin Receptor Antagonists , Animals , Biotransformation , Biphenyl Compounds/isolation & purification , Chromatography, High Pressure Liquid , Humans , Hydroxylation , Imidazoles/isolation & purification , Liver/metabolism , Losartan , Macaca , Magnetic Resonance Spectroscopy , Rats , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, Ultraviolet , Tetrazoles/isolation & purificationABSTRACT
A novel cytochalasin, L-696,474, (18-dehydroxy cytochalasin H) that inhibits HIV-1 protease was discovered in fermentations of a bark-inhabiting Ascomycete, Hypoxylon fragiforme. The product was first identified from extracts of an agar medium. Fermentation studies on a number of media indicated that the product can be made on several solid and liquid media. Optimum production was obtained from growth in a complex medium composed of glycerol, glucose, citrate, Ardamine, soybean meal, tomato paste, and inorganic salts. Other Hypoxylon spp., related species of Xylariales, and other fungi known to produce cytochalasins, were also surveyed for their ability to make L-696,474. Only one other Hypoxylon fragiforme isolate was found to make this novel cytochalasin; none of the other cultures surveyed made L-696,474 or any other compounds which inhibit HIV-1 protease.
Subject(s)
Ascomycota/chemistry , Cytochalasins/isolation & purification , HIV Protease Inhibitors , Cytochalasins/pharmacology , Fermentation , IsoindolesABSTRACT
The immunosuppressants FK506 and FR 900520 were desmethylated by Actinoplanes sp. ATCC 53771 to yield various O-desmethylated products. The products were isolated and purified by solvent extraction and HPLC chromatography, and identified by NMR and MS spectroscopy.
Subject(s)
Actinomycetales/metabolism , Immunosuppressive Agents/metabolism , Piperidines/metabolism , Tacrolimus/metabolism , Animals , Cells, Cultured , Chromatography, High Pressure Liquid , Fermentation , Immunosuppressive Agents/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Methylene Chloride , Mice , Molecular Conformation , Molecular Structure , Piperidines/chemistry , Spectrometry, Mass, Fast Atom Bombardment , T-Lymphocytes/drug effects , Tacrolimus/chemistrySubject(s)
Antifungal Agents/isolation & purification , Animals , Antifungal Agents/pharmacology , Cryptococcosis/drug therapy , Cryptococcus neoformans/drug effects , Female , Fermentation , Fungicides, Industrial , Fusarium/metabolism , Magnetic Resonance Spectroscopy , Mice , Microbial Sensitivity Tests , Organic ChemicalsABSTRACT
In screening for new antifungal agents from fungi, a new lipopeptide antifungal agent, L-671,329, similar to echinocandin B, has been isolated from Zalerion arboricola. Studies indicate that L-671,329 is produced under both solid and liquid fermentation conditions.
Subject(s)
Anti-Bacterial Agents , Antifungal Agents/isolation & purification , Peptides , Antifungal Agents/pharmacology , Candida albicans/drug effects , Candida albicans/growth & development , Chromatography, High Pressure Liquid , Echinocandins , Fermentation , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/pharmacologyABSTRACT
The discovery and biological properties of four novel cholecystokinin antagonists produced by Aspergillus alliaceus is described. One of these was seven times more potent than the previously reported asperlicin.
Subject(s)
Aspergillus/metabolism , Benzodiazepinones/isolation & purification , Cholecystokinin/antagonists & inhibitors , Fermentation , Animals , Benzodiazepinones/biosynthesis , Benzodiazepinones/pharmacology , RatsABSTRACT
Difficidin and oxydifficidin, two novel macrocyclic polyene lactone phosphate esters were discovered in fermentation broths of each of two strains of Bacillus subtilis: ATCC 39320 and ATCC 39374. Difficidin and oxydifficidin each showed a broad spectrum of activity against aerobic and anaerobic bacteria. Many of the susceptible aerobes and anaerobes were human pathogens resistant to one or more antibiotics. Difficidin and oxydifficidin when administered intraperitoneally protected mice against an otherwise lethal bacteremia caused by Klebsiella pneumoniae (ED50 in mg/kg of 1.31 and 15.6 respectively). Neither difficidin nor oxydifficidin were effective when administered via the subcutaneous route.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Bacillus subtilis/analysis , Animals , Anti-Bacterial Agents/pharmacology , Bacteria, Aerobic/drug effects , Bacteria, Anaerobic/drug effects , Fermentation , Klebsiella Infections/drug therapy , Klebsiella pneumoniae/drug effects , Lactones/isolation & purification , Lactones/pharmacology , MiceABSTRACT
L-681,217 is a new broad spectrum antibiotic isolated from fermentation broth. The compound is a structurally unique member of the efrotomycin family of growth permittant antibiotics.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Chemical Phenomena , Chemistry , Chromatography, High Pressure Liquid , Esterification , Fermentation , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Pyrans/isolation & purification , Pyrans/pharmacology , Pyridones/isolation & purification , Pyridones/pharmacology , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Streptomyces/metabolismABSTRACT
The fermentation and isolation of a new, non-peptide cholecystokinin antagonist, asperlicin, produced by Aspergillus alliaceus is described. The potent and specific interaction of asperlicin with cholecystokinin receptors was shown using in vitro biochemical assays.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Aspergillus/metabolism , Benzodiazepinones/isolation & purification , Cholecystokinin/antagonists & inhibitors , Receptors, Cell Surface/drug effects , Animals , Anti-Bacterial Agents/pharmacology , Benzodiazepinones/pharmacology , Chemical Phenomena , Chemistry , Fermentation , In Vitro Techniques , Rats , Receptors, Cell Surface/metabolism , Receptors, CholecystokininABSTRACT
A new, competitive, nonpeptide cholecystokinin (CCK) antagonist, asperlicin, was isolated from the fungus Aspergillus alliaceus. The compound has 300 to 400 times the affinity for pancreatic, ileal, and gallbladder CCK receptors than proglumide, a standard agent of this class. Moreover, asperlicin is highly selective for peripheral CCK receptors relative to brain CCK and gastrin receptors. Since asperlicin also exhibits long-lasting CCK antagonist activity in vivo, it should provide a valuable tool for investigating the physiological and pharmacological actions of CCK.
Subject(s)
Aspergillus/metabolism , Benzodiazepinones/isolation & purification , Cholecystokinin/antagonists & inhibitors , Animals , Benzodiazepinones/pharmacology , Chemical Phenomena , Chemistry , Cholecystokinin/pharmacology , Cholecystokinin/physiology , Dose-Response Relationship, Drug , Gallbladder/drug effects , Guinea Pigs , Ileum/drug effects , Pancreas/drug effects , Rats , Receptors, Cell Surface/drug effects , Receptors, CholecystokininABSTRACT
A new antiparasitic macrolide, L-155,175, produced by a strain of Streptomyces hygroscopicus, has been isolated; its structure was determined by physico-chemical means. It is active against the tapeworm Hymenolepis diminuta in rats.
Subject(s)
Antiprotozoal Agents/isolation & purification , Antiprotozoal Agents/analysis , Chemical Phenomena , Chemistry , Culture Media/analysis , Fermentation , Magnetic Resonance Spectroscopy , Soil Microbiology , Solvents , Streptomyces/analysis , Streptomyces/metabolism , Structure-Activity RelationshipABSTRACT
The maximum yield for the production of L-681,110 by Streptomyces sp. MA-5038 (ATCC 31587) was observed after 5 days' incubation at 28 degrees C and pH about 8.3. L-681,110 was isolated from the fermentation broth by acetone extraction of the mycelia, absorption to Amberlite XAD-2 resin and two separations by thin-layer chromatography. The structure of L-681,110 was found to consist of a sixteen-membered lactone with a new type of substitution. The inhibition of ATPase, activity against Caenorhabditis elegans and stimulation of gamma-aminobutyric acid release indicate that L-681,110 possesses some characteristics of both oligomycin and avermectin. L-681,110 was also active against tapeworm and ticks in an in vivo assay.
Subject(s)
Lactones/isolation & purification , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Streptomyces/metabolism , Animals , Brain/drug effects , Caenorhabditis/drug effects , Cestoda/drug effects , Fermentation , Guinea Pigs , In Vitro Techniques , Lactones/pharmacology , Male , Rats , Ticks/drug effects , gamma-Aminobutyric Acid/metabolismABSTRACT
A new unsaturated glutamic acid analog, 4-amino-3-chloro-2-pentenedioic acid ( ACPA ) was isolated from a fermentation broth produced by a strain of Streptomyces. ACPA has a very narrow antibacterial spectrum, which is virtually limited to Micrococcus luteus.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Bacillus subtilis/drug effects , Chemical Phenomena , Chemistry , Fermentation , Glutamates/isolation & purification , Glutamates/pharmacology , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Micrococcus/drug effects , Streptomyces/metabolism , X-Ray DiffractionABSTRACT
The epithienamycins are cell wall active antibiotics structurally related to N-acetylthienamycin. We have found forty-three isolated of Streptomyces flavogriseus which are capable of producing members of the epithienamycin family. Six major epithienamycin components, and xanthomycin, have been isolated from fermentation broth. Fermentation conditions can be varied to enrich for certain members of the epithienamycin family. All six components show activity in vitro versus a broad spectrum of bacterial species. The weight potencies vary 27 fold from the most active to least active.