• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    A novel Antibiotic G-6302 is produced by cultivating a microorganism belonging to the genus Pseudomonas and being capable of producing Antibiotic G-6302 in a culture medium to have Antibiotic G-6302 elaborated and accumulated in the cultured broth and recovering the antibiotic. Antibiotic G-6302 is useful as a germicide or disinfectant.
    公开号:SU1003761A3
    申请号:SU782704454
    申请日:1978-12-28
    公开日:1983-03-07
    发明作者:Имада Акира；Китано Казуаки；Асаи Мицуко
    申请人:Такеда Кемикал Индастриз,Лтд (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING ANTIBIOTICS The invention relates to the microbiological industry and concerns a method for preparing the antibiotic G-6302. The purpose of the invention is to provide a method for producing antibiotic G-6302. This goal is achieved by the fact that, according to the method for producing an antibiotic of the formula uHi uKj f n f n 7-, HOit-t-CHj-tHi-t-1J-Utl JH OHO, the Pseudomonas acedophila G-6302 ATCC-31363 strain is cultivated under aerobic conditions x in a nutrient medium containing sources of nitrogen, carbon and mineral salts, followed by separation of the culture fluid and release of the target product. In this case, in order to raise the yield of the desired product, the cultivation is carried out on a nutrient medium containing additionally methionine, cytin, cystine, sodium sulfate or sodium sulfate. The strain Pseudomonas G-63D2 you are used to investigate the method is G-6302 divided from soil samples collected in the Ashigar Chimon-Gong region, Kanagawa Prefecture, Japan, deposited with the Institute of Fermentation, Osaka (1st) under number I of HE 13774 and characterized by the following characteristics. . Vulturapno-morphological signs. After 2 days on a nutrient canted agar at 28 C, the cells acquire the shape of rods 0.7-1.0 microns in diameter and 0.7-3.5 microns long. Motile with a polar located flagellar zoospore or a polar located flagellum, non-polymorphic. Nonporulatory: without accumulation of polybeta-hydroxybutyric acid as an intracellular carbon reserve. Gram-negative, acid-resistant. When grown at 28 ° C for 1-14 days, it exhibits the following properties. On nutrient agar forms round colonies with a diameter of 1-3 mm with full clearance of the edges after 3 days; homogeneous: opaque / white, no soluble pigment.
    Nutrient agar. Growth moderate, filamentous, opaque, cream color.
    Liquid nutrient medium. Turbid neoplasm, practically without sedimentation. After 14 days of cultivation, it forms a thin stalk.
    Nutritious gelatinous column. Superficial growth, without liquefaction.
    Physiological and biochemical properties
    Litmus milk does not change em. Nitrates in nitrites do not restore. Denitrification is negative. Test for methyl red is negative. The sample of Voges-Prokauer is rational. Hydrogen sulfide forms (if a positive reaction occurs), starch does not hydrolyze. Potassium nitrate absorbs poorly, ammonium sulphate assimilates em. The pigment does not form, U.rease is positive, oxidase is negative, catalase is positive.
    It grows at pH 4-8, the optimum pH is 4.5-6, about; temperature from 2 to 31 ° C, the optimum growth at 25-30 ° C.
    Aerobe. Oxidative enzyme test - oxidative.
    On environments with sugars weakly forms acid, gas does not form.
    Assimilation of carbon sources; it absorbs arabinose, D-xyloZU, O-glucose, D-mannose, D-fructose, maltose, sucrose, trehalose, 0-sorbitol, O-mannitol, inositol, glycerol, alpha methyl-D-glucoside, adonite raffinose, cis aconitate, citrate, isocitrate, gluconate, acetate, fumara malate, tartrate, p-hydroxybenzonate, o (. - alanine, beta-alanine, L-isoleucine succinate, 2-ketogluconate.
    Does not digest lactose, starch, melibiosis, dulcite, L-valine.
    Malonat does not use.
    Phenylalanine does not deaminate.
    Decarboxylase activity; arginine is negative, lysine is negative, and ornithine is negative.
    Esculin hydrolyzes.
    The content of guanine-cytosine in deoxyribonucleic acid is 59.5 mol%.
    The method is carried out as follows.
    For the cultivation of strain G-630, carbon sources such as glucose, sucrose, pulp, molasses, glycerin, oils and fats, and organic acids can be used. As a source of nitrogen, organic and inorganic nitrogen-containing compounds, for example, soybean flour, cotton seed flour, corn extract, dry yeast, yeast extract, meat extract, urea, ammonium sulfate
    ammonium nitrate, ammonium chloride, ammonium phosphate. Inorganic salts are sodium chloride, potassium chloride, calcium carbonate, magnesium sulphate, primary acidic potassium phosphate, secondary acidic sodium phosphate. The output of the antibiotic can be increased by adding sulfur compounds — sodium sulfate, thiosulfates, sulfur-containing amino acids — cysteine, cystine, megionin. Concentrations of sulfur compounds are maintained in the nutrient medium at a level of 0.01-1.0% (wt.ab.), Preferably 0.02-0.5% (wt.ab.). Salts of heavy metals, in particular ferrous sulfate, copper sulfate, as well as vitamin B, biotin, can be introduced into the nutrient medium. Cultivation in a liquid medium is carried out under stationary conditions with stirring, shaking under aerobic conditions. The cultivation temperature is from 15 to, the pH of the nutrient medium is 4-8. The cultivation is carried out for 8-168-4, preferably from 24 to 144 h.
    The antibiotic can be isolated by the ordinary methods used in the isolation of antibiotics, namely, cell separation by centrifugation followed by purification of the target product by dissolving in a solvent or by precipitation from solution, ion exchange chromatography, etc.
    Example. Cells of the microorganism Pseudomonas acidophila G-6302 (FERM-P 4344, I GO 13774,: 7 TSS-31363) grown on nutrient agar are used to ionoculate two .h. Sakaguchi flasks containing 500 vol. medium, which includes 1% glucose, 0.5% polypton product, 0.5% microacid extract, 0.5% sodium chloride, pH 7.0, after which each flask is incubated on a return-access shaker with 28 ° C for 48 hours. The final culture is used as a seed culture.
    Fermenter from stainless steel with a capacity of 200 X 10 about. hours filled 120 x 10 ob.h. medium that includes 3% glycerol, 0.1% glucose, 0.5% polypeptone, 0.5% mineral extract, and 0.5% sodium chloride, and after adjusting the pH to 7.0 by adding 30% - Its aqueous solution of sodium hydroxide is rterilized with water vapor at 120 s for 20 min. Then the medium of the sterilized vessel is inoculated with the specified seed culture and incubated at 28 ° C with aeration at a feed rate of 120 x X 10 ob. / Min. Rotation speed of the stirrer 180 rpm for 78 hours. The final broth is centrifuged using a separator centrifuge in a smooth operating mode to separate the cell mass, as a result, 110 X 10 ob.ch are obtained. . top layer of fluid. The pH of this liquid is adjusted to .4.2 and passed through a column of 15 x 10 v activated charcoal. The wash is washed 45 x 10 ob.h. 50% aqueous solution of acetone, the electrolyte is collected in the form of 10 x 10 ob.h. fractions. Fractions 2 and 3, showing activity against Proteus mirabilis, are selected, 20 x 10 vol are added. water and the mixture is passed through cola ku, filled with 10 x. 10 ob.ch. Resins Dauks (chlorinone form). The column is washed 25-10ob.h. water and elute 50 J 10 ob.h. 5% sodium chloride aqueous solution. The active fractions are taken, the pH is adjusted to 4, O and again passed through a column with activated charcoal (8 hours). Column washed 2410 ob.h. water and elute with a 20% aqueous solution of methanol (volume / / volume). The active fractions are taken and the concentration is concentrated to 50 vol.h. under reduced pressure. Then add 200 rpm. acetone, the precipitate is filtered off, washed with 50 about.h. acetone and 100 ob.h. diethyl ether and dried under reduced pressure. Get 12 parts of the crude product. B500 ob.ch. 0.01 M phosphate buffer (pH 6.6) dissolve the crude product and pass the solution through a column of 200 parts by volume. product DEVE-Sephadex A-25, pre-treated with buffer. The column is washed with 400 rpm. of the same buffer, and then eluted with the same buffer, to which 0.5% sodium chloride was previously added. The active fractions are selected, the pH is adjusted to 3.21 n. HC1 and passed through a column of 60 rpm, h, activated charcoal. The column is washed with 200 rpm. water and 100 ob.ch. 20% (v / v) aqueous methanol with subsequent elution with 50% aqueous acetone (v / v). The active fractions are collected, concentrated under reduced pressure and dissolved in 5 parts by volume. methanol. 100 vol. Parts of acetone is added, the mixture is kept cold. The precipitate formed is separated by filtration, washed with diethyl ether and dried under reduced pressure with phosphorus pentoxide at 40 ° C for 6 hours. 3.8 parts of powder are obtained. The antibiotic has the following physicochemical properties. Melting point 120 ° C (sintering), 1. (with decomposition). White Pors ook. Molecular weight 400 + 20 (titrometers). Found,%: C 34.83-35.45, H 5.41-5.24; N 13.22-13.73-, S 7.65-7.75, O 38.13 + 0.5. C H N. S O- H. O - (i 2.0 4- 9 2 Ultraviolet absorption spectrogram: only final absorption frequencies (no characteristic absorption at a wavelength above 210 nm). Infrared absorption spectrogram, dominant peaks (potassium bromide), cm : 3440 (si), 2920 (sr), 2850 (sr), 2600 (sl 1770 (si), 1650 (si),; i530 (si), .1458 (sr), 1390 (ate) 1340 (ate), 1280 (pl), 1240 (si), 1210 (pl), 1180 (wed), 1118 (ate), 1043 (si), 792 (ate), 632 (s), where si is strong, cf. average, ate - weak absorption, pl - shoulder. Specific rotation (the plane of Ttolizaizi.ii) W 1 3 + 94 ° + 10 (C-0.35, water). Spectrogram of a nuclear magnetic resonance (in dimethyl sulfoidea, 100 MHz) 5 3.31 ppm (S is a certain chemical unit in the direction of 0-CH ,,). Is not soluble in petroleum ether, hexane, diethyl ether, benzene, ethyl acetate and chloroform J is moderately soluble in ethanol, pyridine and acetone, soluble in methanol and dimethyl sulfoxide; easily soluble in water. Color reactions: positive with ninhydrin and potassium permanganate, negative - with ferric chloride - potassium ferricyanide, Sakaguchi and Molisha) Uncertainly positive - Ehrlich reaction. It is resistant in an aqueous solution in the range of pH values 3–7 at 60 s for 10 min, unstable at a pH above 8.5. Acid reaction. Example 2. In a fermentation vessel of stainless etal; capacity ob.ch. load 35 10 ob.ch. medium which contains 3% glycerol, 0.1% glucose, 0.5% polypeptone, 0.5% mineral extract, 0.5% sodium chloride, then the pH of this medium is adjusted to 7.0 by adding 30% aqueous solution of sodium hydroxide and is sterilized with water vapor for 20 1in. Then the medium is inoculated by the producer. Incubated at a temperature of 2B ° C with aeration at an ekoreeti supply of 3510 vol. h, / min, and rotation of the agitator 180 rpm for 48 h, obtaining a secondary culture. Fermentation stainless steel tank with a 2001P container ob.h. fill 120010 ob.h. medium, which includes 3% glycerol, 0.1% glucose, 0.5% polypeptone, 0.5% mineral extract, 0.5% sodium chloride and OD% sodium thiosulfate, and after adjusting the pH to 7.0 by adding 30 % solution of sodium hydroxide is sterilized with water vapor for 20 minutes. Then the medium is inoculated with a secondary seed culture. The inoculated medium is incubated at 28 ° C with aeration at a feed rate of 1200.10 and rotation speed of the stirrer 180 rpm for 90 cr as a result receive 115010 obach. culture liquid., 40-10-10 parts of the product Hiflo-Supr-Sel are added to it and filtered with the help of a Lillot press. The filter size is adjusted to 4, 2 by adding 4 n, m gropropuska through a column with 120- 10 ok, h activated charcoal. The column is washed 30010 about, h water, elute with 50% (v / v) aqueous acetone solution. The active fractions are removed and concentrated under reduced pressure to remove acetone. The resulting aqueous concentrate was diluted with 200 10 vol, h. water and passed through a column filled with 5010 ob.h. product Dianon (chlorinone form). Column Pro1 is filled with a 1% aqueous solution of sodium chloride. The active fractions are collected and concentrated under reduced pressure to a final volume of 100 parts by volume, after which 210 vol% is added, h. methanol and precipitated sodium chloride is filtered off. After that, the filtrate is concentrated under reduced pressure to a volume of 200 parts by volume, and then 2-10 vol. Hours, acetone is added, the precipitated B precipitate is filtered off and dried. 757 hours of crude product is obtained, 500 hours of crude product. dissolve in. water, bring the values from OH to 4.0, and adsorb to the column on activated charcoal (510-ob.). The active component is eluted by the method of gradient elution using U-10 vol. h, water, and 10 10 about, h methanol aqueous solution (v / v) and the eluate is collected with l-io ob. fractions. The active fractions are collected, concentrated under reduced pressure to remove methanol and the volume is adjusted to blOr by adding 0.01 M phosphate buffer (pH b |, 0). A test solution, G1l adsorption is passed through a column with 3-10 ob.h. the product DEAB-C Fadex prepared according to Example 1, then the column is filled with by-product, h, the same bu, fer, and elution is performed with the same buffer, to which 0.5% sodium chloride is added, the eluate is collected in the form of 500 ob.ch. fractions. The active fraction is taken, the pH is adjusted to 3 with 1N, HC1 and passed through a column with 0.5-10 parts by volume. activated charcoal. Column washed 2-10 ob.h. water and 210 vol.h, a 20% aqueous solution of methanol (vol / vol), and then eluted with 50% aqueous acetone (vol / vol). Select 200 ob.ch. fractions. The active fractions are concentrated under reduced pressure and dissolved in 300 parts by volume. methanol. Add 3 -10 ob.h. acetone and 4 "oh of h, diethyl ether and left in the cold, the precipitated antibiotic is filtered off, washed with diethyl ether and dried under reduced pressure over phosphorus pentoxide. Output 72 g. Data of elementary analysis,%: C 35.45, H 5.24, N 13.73, S 7.75 (w / w). Example 3. In 90 ob.ch. 4.0 parts of antibiotic G-6302 are dissolved in free form (according to examples 1 and 2} in the cold and approximately 9.0 parts by volume of 1N aqueous NaOH solution are added to the solution. Then an additional amount of 1N is added. NaOH solution until pH = 6.5. The solution is freeze-dried and 4.2 G monosodium salt G-6302 is obtained in the form of a white powder. Physico-chemical properties. There is no definite melting point (turns brown at 170 ° C). White powder. Molecular weight 438 ± 5. Found,%: C 33.08, H 5.07, N 12.73, S 7.33, Na 5.18. About Calculated,%: C, 33.03, H 4.85, N 12.84, S 7.35, Na 5.27. Ultraviolet absorption spectrum: only final absorption. Infrared absorption spectrogram, dominant peaks (potassium bromide), cm: 3430 (si), 3250 (pl ), 3000 (cf.), 1770 (si), 1640 (si), 1530 (si), 1450 (ate), 1405 (ate), 1343 (ate),), 1245 (si), 1180 (ate), 1118 (ate), 1050 (s), 820 (ate), 782 (ate), 632 (s). Specific rotation: Icil + 85 ° + t Yu (C-0.37, water). Insoluble in petroleum ether, hexane, diethyl ether, benzene, ethyl acetate, chloroform and acetone; It is poorly soluble in methanol, ethanol and pyridine; it is soluble in dimethyl sulfoxide and is easily soluble in water. Color reactions. Positive with ninhydrin and potassium permanganate, negative - with ferric chloride - potassium ferricyanide, Sakaguchi and Molisha, indefinitely positive - Erlich reaction. Racks in aqueous solution in the range of pH values 3-7 with heating for 10 minutes; unstable at pH values above-8.5. Example 4. Cells of the microorganism G-6302 grown on nutrient agar agar are used to inoculate a nutrient medium (40 parts by volume) containing 1% glucose, .0.5% polypeptone, 0.5% meat extract and 0 , 5% sodium chloride (pH 7.0), then the flask is incubated with inoculated medium on a rotary shaker at 28 ° C for 48 hours and a seed culture is obtained. Conical flasks with a capacity of 200 rpm. fill 40 ob.h. a medium containing 3% glycerol, 1% glucose, 0.5% polypeptone, 0.5% mineral extract and 0.5% sodium chloride (pH 7.0), 0.020, 5% different sulfur compounds are added to each flask with nq following incubation on a rotary agitator at 28 s for 96 4 Additional administration of sulfur compounds allows an increase in the yield of the antibiotic (from 15 µg / ml on ordinary medium to 20-80 µg / mp with the addition of common sulfur-containing compounds) Pr and measure 5 In 7.5 about. 1 part of the antibiotic is dissolved in the free form with cold aqueous solution, then 17.5 vol. cold methanol. The mixture was left in the cold for 28 hours. A powder crystallized as colorless crystals was obtained. KrisAntimikrobny range of G-6302 and its sodium salt
    Microorganism
    Esche r i ch i a coli N IHJ Escherichia coli T-7 Salmonella typhosa Boxhi11 58 Shigella flexnerl EW-10 Klebsiella pneunoniae DT Proteus vulgaris I FO 3988 Proteus morganic IFO 3849 Proteus mirabilis IFO 3847
    Minimal inhibitory
    22ITS§ 1SP x 5/5 0
    G-6302 and G-6302 a
    25 25
    25 25
    12.5
    12.5 25 12.5 25
    12.5 100 100 100 100 25 25 100 100 above 100 The above 100 talons are separated, washed with a small amount of 80% (v / v) cold aqueous methanol, then successively dried with cold methanol and diethyl ether over reduced pressure and a temperature of 60 ° C for 6 hours and 0.930 parts of the crystals obtained with the antibiotic are added. The resulting crystals have the following physicochemical properties. The melting temperature is from 168 to 170 s. Found: C 35.51-35.56, H 5.615, 61, N 12.93-12.93, S 7.45-7.59. N, 50, CH ,, OH 0.5, It c35.69; P 5.76; N 12.81, S 7.33. 23 Specific rotation:, + 82 + + (C 1.0, in water). Infrared absorption spectrum, dominant peaks (potassium bromide), 3440, 3355, 3000, 1780, 1660, 1650, 1538, 1265, 1245, 1220, 1038, 625. Spectrogram of nuclear magnetic resonance (in dimethyl sulfoxide, 100 MHz); 3.31 ppm (SiBS) (certain chemical shift towards 0-CH G-6302). tf 3,320 ppm (.) (a certain chemical shift towards -o-CHj of methanol, which is contained in crystals. talles) .. The antibiotic G-6302 and its sodium salt are active against gram-negative and some gram-positive bacteria (see table).
    Table continuation
    The proposed method makes it possible to obtain an antibiotic used to treat diseases caused by the listed microorganisms, as well as a germicide or disinfectant.
    权利要求:
    Claims (2)
    [1]
    1. A method for preparing an antibiotic of formula
    Mr. JH, 1
    BOjt-U- (iHi-CHi- (i-N- i-i-S “-n,
    fl 8 l o
    The Pseudononas acedophila G-6302 ATCC-3136 strain is cultivated under aerobic conditions in a nutrient medium containing sources of nitrogen, carbon and mineral salts, followed by separation of the culture fluid and the separation of the target product.
    [2]
    2. The method according to claim 1, characterized in that in order to increase the yield of the target product, the cultivation is carried out on a nutrient medium containing additionally methionine, cysteine, cystine. sodium sulfate or sodium thiosulfate.
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    同族专利:
    公开号 | 公开日
    FR2413399B1|1982-11-19|
    FR2413399A1|1979-07-27|
    IT1202812B|1989-02-09|
    ES476480A1|1979-04-16|
    DE2855949A1|1979-07-05|
    CS208768B2|1981-09-15|
    BE873217A|1979-06-29|
    AU521534B2|1982-04-08|
    PH15534A|1983-02-09|
    JPS6046955B2|1985-10-18|
    CA1113873A|1981-12-08|
    DK147452B|1984-08-13|
    DK147452C|1985-02-18|
    HU179350B|1982-10-28|
    IT7831423D0|1978-12-29|
    AU4230778A|1979-07-05|
    SE433229B|1984-05-14|
    DK582978A|1979-07-01|
    CH644593A5|1984-08-15|
    DE2855949C2|1987-06-04|
    US4229436A|1980-10-21|
    ZA786882B|1980-02-27|
    GB2011380B|1982-08-18|
    SE7813384L|1979-07-01|
    GB2011380A|1979-07-11|
    JPS54163501A|1979-12-26|
    NL7812493A|1979-07-03|
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    US4775670A|1980-09-29|1988-10-04|E. R. Squibb & Sons, Inc.|2-oxo-1-azetidinesulfonic acid salts|
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    US4675397A|1980-12-05|1987-06-23|Takeda Chemical Industries, Ltd.|1-sulfo-2-oxoazetidine derivatives and their production|
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    US4572801A|1981-04-30|1986-02-25|Takeda Chemical Industries, Ltd.|4-Carbamoyloxymethyl-1-sulfo-2-oxoazetidine derivatives and their production|
    JPH0154358B2|1981-07-07|1989-11-17|Takeda Chemical Industries Ltd|
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    法律状态:
    优先权:
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    JP52160308A|JPS6046955B2|1977-12-30|1977-12-30|
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