Hybrid Antibiotics Based on Azithromycin and Glycopeptides: Synthesis and Antibacterial Activity.

A series of hybrid antibiotics on the basis of azithromycin and glycopeptides with the glycopeptide molecule attached via the aminoalkylcarbamoyl spacer to 11-position of the macrolide was synthesized. All the synthesized compounds demonstrated equal or superior to azithromycin and vancomycin antibacterial activity against 7 tested strains of grampositive bacteria. The new hybrid antibiotics were more active than azithromycin or vancomycin against S.pneumoniae ATCC 49619. Some of the compounds were active against E.faecium and E.faecalis strains resistant to vancomycin.

Antitumor and Antioxidant Properties of Water-Soluble Polysaccharides from Submerged Mycelium of Flammulina velutipes.

The aim of the study was to evaluate antitumor and antioxidant properties of water-soluble polysaccharides from submerged myceliumn of Flammulina velutipes grown under optimized conditions. The optimization of the nutrient medium composition allowed to increase the biomass yield by more than 2 times (up to 35 g/l) and to reduce the time of the cultivation process. The submerged mycelium of F.velutipes strain Fv-1 contained 14.8% of a water-soluble polysaccharides, 31.6% of proteins, 2.5% of total lipids, vitamins B (B1, B5, B6). The polysaccharides contained glucose, galactose, fucose, mannose, xylose, rhamnose. The proteins contained all the essential amino acids except for tryptophan. Dry powder of the submerged mycelium, water extract of the mycelium and total fraction of the water-soluble polysaccharides demonstrated the antitumor activity against murine lymphocytic leukemia P 388 in vivo. The antitumor activity of the substances was mainly due to the polysaccharides, since their purification increased the tumor growth inhibition. The maximum tumor growth inhibition by the water-soluble polysaccharides amounted to 94%. The total fraction of the water-soluble polysaccharides from F.velutipes strain Fv-1 demonstrated antioxidant activity. The antioxidant capacity (AOC) of the water-soluble fraction from F.velutipes was higher than that of the water-soluble polysaccharides from the sub- merged mycelium of Grifolafrondosa, but inferior to the AOC of the water-soluble polysaccharides from the submerged mycelium of Ganoderma luciduma.

[Assessment of Antitumor Effect of Submerged Culture of Ophiocordyceps sinensis and Cordyceps militaris].

Ophiocordyceps sinensis and Cordyceps militaris metabolites showed a high potential in the treatment of tumors as well as some other diseases. Antitumor properties of O. sinensis and C. militaris submerged mycelium were investigated. It was found that the O. sinensis dry biomass in a dose of 50 mg/kg administered once a day to the mice with subcutaneously inoculated P388 lympholeucosis lowered the tumor growth by 65% vs. 54% for the C. militaris dry biomass. The water extract of O. sinensis submerged culture however accelerated the growth of the P388 lympholeucosis tumor node in the mice almost two times, compared to the control. A greater caution in using this fungus as a source of biologically active substances is required since unwanted tumor-stimulating effects can arise.

[Design of Novel Carboxamides of Eremomycin and Vancomycin with 4- or 3-Amino Methyl Phenyl Boric Acid and Their Investigation].

Amidation of the end carboxyl group of eremomycin and vancomycin by pinacolinic 4- or 3-amino methyl phenyl boron acids esters in the presence of the condensing reagent PyBOP resulted in formation of novel carboxamides of the antibiotics (IIIa-VIa). After elimination of the pinacolinic group under mild hydrolysis in weak acid aqueous medium there formed the respective derivatives with a residue of the nonprotected boric acid (III-VI). It was shown that the activity of the 4-substituted derivatives of the borole-containing eremomycin and vancomycin practically was the same as that of the initial antibiotics, while higher than that of the respective 3-substituted derivatives of the borole-containing derivatives against 8 strains of grampositive bacteria.

[Antimicrobial Properties of Eremoxylarin A Produced by Ascomycete of Sordariomycetes in Submerged Culture].

The fungal strain INA 01108 producing antibiotic substances with broad spectrum of antibacterial activity was isolated from the natural environment. By the morphological characteristics and DNA analysis it was shown to belong to Ascomycetes of Sordariomycetes. In submerged culture the strain produced at least four antibiotics. The major component of them was identified as eremophilane-type sesquiterpene eremoxylarin A. Eremoxylarin A is effective in vitro against grampositive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin group glycopeptide antibiotics resistant Leuconostoc mesenteroides VKPM B-4177. The efficacy and toxicity of eremoxylarin A was determined on a murine staphylococcal sepsis model. The dose of 6.25 mg/kg provided 100% recovery and survival of the animals, while the dose of 3.12 mg/kg was close to the ED50. The chemical structure of eremoxylarin A allows to modify the antibiotic and such studies may be relevant to design a less toxic derivative without loss of the valuable antimicrobial properties.

[Antitumor Activity of Polysaccharides from Ganoderma lucidum Mycelium: in vivo Comparative Study].

Fractions of water soluble and alkali soluble polysaccharides, as well as fucogalactan, a water soluble polysaccharide, and xylomannan, an alkali soluble polysaccharide, were isolated from the Ganoderma lucidum submerged mycelium. When administered orally, the polysaccharides showed antitumor activity in vivo on murine models of solid tumors. Xylomannan and fucogalactan showed the highest antitumor activity. Sensitivity to xylomannan was more pronounced in adenocarcinoma Ca755 as compared to the T-cell lymphocytic leukemia P388. The antitumor activity of the water soluble polysaccharides total fractions from the mycelium and fruiting bodies of the G. lucidum strain was almost identical. The maximum antitumor effect of the mycelium water soluble polysaccharides total fraction was observed with the use of the daily dose of 2 mg/kg.

[Preparation and biological properties of basidiomycete aqueous extracts and their mycelial compositions].

The basidiomycetes Ganoderma lucidum, Hericium erinaceus, Lentinus edodes and Trametes versicolor were used for preparation of aqueous extracts. A polysaccharide preparation (VPG) was isolated from the G. lucidum aqueous extracts. The mycelium was grown under submerged conditions according to an original procedure. Preliminary exposure of mice with tumors to cyclosphosphamide in a low dose for prolonged elimination of T-suppressors and rapid recovery of T-killers induced an increase in the efficacy of the H. erinaceus and L. edodes extracts. Investigation of the aqueous extracts and VPG on different tumor strain lines for the potential Modifiers of Biological Response (Ca755, s/c P388, s-180) demonstrated antitumor activity and satisfactory tolerabily after oral administration. Inhibition of the tumor growth by the H. erinaceus and T. versicolor extracts and VPG amounted to 88-99% and that of s-180 treated with the L. edodes aqueous extract amounted to 66-75%. Compositions 1, 2, 4 amd 5 were significantly more active by the duration and value of the effect on the animal tumor nodes as compared to the aqueous extracts and VPG included to the compositions and composition 4. Composition 5 (T. versicolor + H. erinaceus + G. Lucidum) proved to be the most efficient by all the criteria. The results of the design of the technologies for cultivation of the mycelum of the medicinal basidiomycetes, investigation of the antumor properties of the extracts and polysaccharide fraction of the mycelium and development of efficient compositions on their basis are summarized. Composition 5 proved to be the most promising for the clinical trials.

[Fortification of antimicrobial barrier of the small intestine in newborn mice after oral administration of ascorbigen].

Ascorbigen, a natural product, is an indole derivative of L-ascorbic acid. Its effect on postnatal development and antibacterial resistance of the small intestine was studied on newborn mice. Ascorbigen was administered to 3-5-day old mice in a dose of 100 mg/kg orally every day for 7-10 days. 30 minutes before the last administration of the drug clinical isolates of Staphylococcus aureus or Escherichia coli were administered intragastrically to the young mice. The animals were killed in 24 hours and the frequency of the isolation of the microbes from the blood, spleen, kidneys and liver was developed. The oral use of the drug normalized the intestinal microflora, provided a reliable decrease of the bacteria isolation from the blood, spleen, kidneys and liver and prevented the animal death. The morphological examination showed that ascorbigen significantly increased the number and activity of the Paneth cells in the gland crypts, the goblet cells in the villi and mononuclear cells in the selfplate of the intestine mucous membrane vs. the intact control.

[Effect of lysozyme on the growth of murine lymphoma and antineoplastic activity of cyclophosphamide]. / Vliianie lizotsima na rost myshinoi limfomy i protivoopukholevuiu aktivnost' tsiklofosfamida.

It was shown that hen egg-white lysozyme (LM) in the dose 100 mg/kg under the daily intragastral use slightly inhibited tumor grown or did not influence significantly upon it and did not change antitumor activity of cyclophosphamide. When used at mice C57Bl/6J with the transplanted ascitic or solid T-cell lymphoma EL4 (syngeneic system). On model of the same tumors in ascitic form at mice-hybrids (C57Bl/6J x DBA2)F1 (semisingeneic system) LM significantly potentiates antitumor activity of cyclophosphamide, though it had no effect on the rate of tumor growth. Potentiation of the effect of cyclophosphamide revealed itself in more slow development of ascite, increased mean life-span and the overall survival, appearance of completely cured animals. Our clinic-laboratory studies have revealed a sharp deficit of endogenic lysozyme in the blood serum of leukemic patients and extremely low lysozyme content in lavage liquid, from leukemic patients, with pneumonia. These data suggest that LM can be useful as a food additive in the complex treatment of oncological patients for enhancing antineoplastic chemotherapy efficacy.