N-(3-Acyloxyacyl)glycines were isolated as N-type calcium channel blockers from a marine bacterium Cytophaga sp. SANK 71996. The identification and fermentation of the producing strain and structure characterization of N-(3-acyloxyacyl)glycines by spectral analyses and chemical syntheses are described together with their antagonistic activities.

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New melanin synthesis inhibitors (MR566A and B) and six related known isocyanocyclopentenes were isolated from the fermentation broth of Trichoderma harzianum. The IC₅₀ values of MR566A and B against mushroom tyrosinase were 1.72 and 47μM, respectively. They inhibited melanin biosynthesis in B16 melanoma cells with MIC values of 0.1 and 2.2μM, respectively. Also isolated from the same culture extract of T. harzianum was a new oxazole (MR93B), which showed no inhibitory activity against mushroom tyrosinase at a concentration of 1.000μg/ml.

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New melanin synthesis inhibitors (MR566A and B) and six related known isocyanocyclopentenes were isolated from the fermentation broth of Trichoderma harzianum, and their structures were elucidated by spectroscopic methods. The structures of novel isocyanides, MR566A (1) and B (2), were elucidated as 1-(3-chloro-1, 2-dihydroxy-4-isocyano-4-cyclopenten-1-yl)ethanol, 1-(1, 2, 3-trihydroxy-3-isocyano-4-cyclopenten-1-yl)ethanol, respectively. The structure of novel oxazole, MR93B (9), was elucidated as 4-[(1Z)-3-hydroxy-2-hydroxymethyl-1-propen-1-yl]oxazole.

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The novel 5, 10-dihydrophencomycin methyl ester (4) and the known microbial metabolites (2-hydroxyphenyl)-acetamide (1), menaquinone MK9 (II, III, VIII, IX-H8) (2), and phencomycin (3a) were isolated from an unidentified marine Streptomyces sp. and the structures were elucidated by NMR methods. Compound 4 shows weak antibiotic activity against Escherichia coll and Bacillus subtilis.

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We describe here the results of a screening program conducted to discover inhibitors of the type-I interleukin-1 receptor (IL-1RI) from samples of microbial origin. An innovative approach, based on automated, nonradioactive receptor binding assays has been employed. Specially prepared cell-free systems have allowed the use of high concentrations of microbial metabolites in the reaction mixtures with a low percentage of false positives. More than 30, 000 microbial samples from different species of soil isolates have been tested and two interesting activities have been purified and characterized. One of these, isolated from Streptomyces sp. GE48009, was identified as niphimycin, an antifungal agent also known as scopafungin. Preliminary evidence suggests that this molecule and azalomycin F, a structural analogue, inhibit IL-1RI by virtue of their long-chain guanidinium moiety. The other activity, isolated from Aspergillus sp. GE49752, was identified as flavipin, a substituted o-phthalaldehyde.

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A novel antitumor antibiotic, UCE6 (1, 3, 8, 10, ll-pentahydroxy-2-methyl-10-(2-oxo-4-hydroxypentyl)naphthacene-5, 12-dione) with topoisomerase I-mediated DNA cleavage activity, was isolated from the culture broth of actinomycetes strain UOE6. Addition of silicone oil antifoam agent, KS69 (2%), to the fermentation enhanced the production of UCE6 by -3 fold. A total of 1.15 g of UCE6 was recovered as reddish orange crystals from a 100 liter fermentation supplemented with 2% KS69. UCE6 exhibited growth inhibitory activity against HeLa S3, HCT116 and Lu-65 cells comparable to that of camptothecin.

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Streptomyces steffisburgensis (NRRL 3193, ATCC 27466) is described as a steffimycin producer. Steffimycin belongs to the anthracycline group of aromatic polyketide antibiotics. The structural analysis of the products accumulated by the wild type ATCC 27466 strain revealed three different forms of 8-demethoxy steffimycin suggesting the loss of C-8 hydroxylation/methylation activity. In our approach to generate new anthracycline molecules, we used this strain as a host in gene cloning. The genes encoding the polyketide ketoreductase and aromatase enzymes of nogalamycin biosynthesis caused the production of 2-demethoxy Steffimycins in S. steffisburgensis.

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The imipenem/cilastatin constitutes a broad spectrum β-lactam antibiotic formulation, especially used in pre and post-operatory treatments for transplanted or drug-immunosuppresed patients. The effect of the dose and the duration of the treatment with imipenem/cilastatin on some parameters of natural immunity in BALB/c mice were examined. The treatment by intraperitoneal route with 1 or 2 g/70 kg/day during 7 days did not alter significantly the parameters tested, whereas the greater dose used (4 g/70 kg/day) had an inhibitory effect on peritoneal cell counts and phagocytic activity, as well as it caused an increase on IL-1 production and natural killer activity. The greater stimulating effect of innate immunity was obtained with the lowest imipenem/cilastatin dose used (0.5 g/70 kg/day). Since this antibiotic apparently does not impair the studied innate immune responses at 1 or 2 g/70 kg/day, it seems to be especially suited for the therapy of systemic bacterial infections in immunocompromised patients.

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A series of derivatives of eremomycin aminomethylated at the 7d position of the resorcinol ring of the amino acid No. 7 was prepared by interaction of eremomycin with formaldehyde and various primary and secondary amines and ammonia. The most active compound obtained was 7d-decylaminomethyl derivative, whose minimal inhibitory concentrations for clinical isolates of staphylococci are 2-8 times lower than those of the parent antibiotic. 7d-Decylaminomethyl derivative was also active against vancomycin-resistant VanA enterococci (8 μg/ml) and Neisseria gonorrhoeae (16 μg/ml).

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Several analogs of hygromycin A were tested in an Escherichia coli cell free protein synthesis inhibition assay and in a Serpulina hyodysenteriae whole cell assay. The aminocyclitol moiety is essential for antibacterial activity in both cell free and whole cell assays. However a 4'-O-allyl ether of hygromycin A aglycone showed an equivalent MIC to hygromycin A, while having a less potent IC₅₀ in the cell free assay. Hence 6-deoxy-5-keto-D-arabino-hexofuranose can be replaced by a hydrophobic allyl group and still retain antibacterial activity. However, this replacement reduces the intrinsic protein synthesis inhibition activity. The loss of intrinsic activity with replacement by the allyl group may be compensated for by better transport into the bacterial cell. In addition to the SAR analysis, we demonstrated that the ineffectiveness of hygromycin A against Gram-negative enteric bacteria such as Escherichia coli is mainly due to the efflux mechanism (Acr A/B pump) existing widely among the enteric bacteria rather than the impermeable barrier of the outer membrane.

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