CN102965420A - Method for producing polypeptide antibiotics nosiheptide through fermentation - Google Patents
Method for producing polypeptide antibiotics nosiheptide through fermentation Download PDFInfo
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- CN102965420A CN102965420A CN2012104691372A CN201210469137A CN102965420A CN 102965420 A CN102965420 A CN 102965420A CN 2012104691372 A CN2012104691372 A CN 2012104691372A CN 201210469137 A CN201210469137 A CN 201210469137A CN 102965420 A CN102965420 A CN 102965420A
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- nosiheptide
- seed
- fermentation
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- FPTCMHOCGKKRGQ-WYOWUDGCSA-N Multhiomycin Natural products CC=C1NC(=O)[C@@H](NC(=O)c2csc(n2)c3cc(O)c(nc3c4csc(n4)[C@H]5CSC(=O)c6[nH]c7cccc(COC(=O)[C@@H](O)C[C@H](NC(=O)c8csc1n8)c9nc(cs9)C(=O)N5)c7c6C)c%10nc(cs%10)C(=O)N[C@@H](C)C(=O)N)[C@H](C)O FPTCMHOCGKKRGQ-WYOWUDGCSA-N 0.000 title claims abstract description 50
- 101800003864 Nosiheptide Proteins 0.000 title claims abstract description 50
- 229950006423 nosiheptide Drugs 0.000 title claims abstract description 50
- 238000000855 fermentation Methods 0.000 title claims abstract description 35
- 230000004151 fermentation Effects 0.000 title claims abstract description 35
- 239000003910 polypeptide antibiotic agent Substances 0.000 title claims abstract description 21
- MQWDKYHFGBWGQZ-JQTJYXGUSA-N nosiheptide Chemical compound N([C@H](C(=O)N\C(C=1SC=C(N=1)C(=O)N[C@@H]1CC(O)C(=O)OCC=2C=CC=C3NC(=C(C3=2)C)C(=O)SC[C@H](NC(=O)C=2N=C1SC=2)C=1SC=C(N=1)C1=N2)=C/C)[C@@H](C)O)C(=O)C(N=3)=CSC=3C1=CC(=O)\C2=C1/NC(C(=O)NC(=C)C(N)=O)=CS1 MQWDKYHFGBWGQZ-JQTJYXGUSA-N 0.000 title claims abstract 14
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000001963 growth medium Substances 0.000 claims abstract description 28
- 239000002609 medium Substances 0.000 claims description 63
- 238000011218 seed culture Methods 0.000 claims description 52
- 238000012262 fermentative production Methods 0.000 claims description 19
- 235000016709 nutrition Nutrition 0.000 claims description 19
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 18
- 239000001888 Peptone Substances 0.000 claims description 18
- 108010080698 Peptones Proteins 0.000 claims description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- 239000008103 glucose Substances 0.000 claims description 18
- 235000019319 peptone Nutrition 0.000 claims description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 16
- 241001655322 Streptomycetales Species 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 13
- 230000001580 bacterial effect Effects 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 10
- 229920001817 Agar Polymers 0.000 claims description 9
- 244000068988 Glycine max Species 0.000 claims description 9
- 235000010469 Glycine max Nutrition 0.000 claims description 9
- 235000019484 Rapeseed oil Nutrition 0.000 claims description 9
- 229920002472 Starch Polymers 0.000 claims description 9
- 229930006000 Sucrose Natural products 0.000 claims description 9
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 9
- 240000008042 Zea mays Species 0.000 claims description 9
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims description 9
- 235000002017 Zea mays subsp mays Nutrition 0.000 claims description 9
- 239000008272 agar Substances 0.000 claims description 9
- 238000004458 analytical method Methods 0.000 claims description 9
- 235000005822 corn Nutrition 0.000 claims description 9
- 239000002504 physiological saline solution Substances 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- 239000008107 starch Substances 0.000 claims description 9
- 235000019698 starch Nutrition 0.000 claims description 9
- 239000005720 sucrose Substances 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 239000002054 inoculum Substances 0.000 claims description 8
- 239000011148 porous material Substances 0.000 claims description 8
- 238000002203 pretreatment Methods 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 230000002623 sporogenic effect Effects 0.000 claims description 8
- 241000187762 Streptomyces actuosus Species 0.000 abstract description 3
- 239000003674 animal food additive Substances 0.000 abstract 1
- 239000013078 crystal Substances 0.000 abstract 1
- 238000011081 inoculation Methods 0.000 abstract 1
- OQAOHXRUMXWDLQ-ATVZKCIHSA-N N-(3-amino-3-oxoprop-1-en-2-yl)-2-[(1S,18S,21Z,28S,30S)-21-ethylidene-9,30-dihydroxy-18-[(1R)-1-hydroxyethyl]-40-methyl-16,19,26,31,42,46-hexaoxo-32-oxa-3,13,23,43,49-pentathia-7,17,20,27,45,51,52,53,54,55-decazanonacyclo[26.16.6.12,5.112,15.122,25.138,41.147,50.06,11.034,39]pentapentaconta-2(55),4,6,8,10,12(54),14,22(53),24,34(39),35,37,40,47,50-pentadecaen-8-yl]-1,3-thiazole-4-carboxamide Chemical compound C\C=C1/NC(=O)[C@@H](NC(=O)c2csc(n2)-c2cc(O)c(nc2-c2csc(n2)[C@@H]2CSC(=O)c3[nH]c4cccc(COC(=O)[C@@H](O)C[C@H](NC(=O)c5csc1n5)c1nc(cs1)C(=O)N2)c4c3C)-c1nc(cs1)C(=O)NC(=C)C(N)=O)[C@@H](C)O OQAOHXRUMXWDLQ-ATVZKCIHSA-N 0.000 description 36
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 3
- 235000011130 ammonium sulphate Nutrition 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000000050 nutritive effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 241000187747 Streptomyces Species 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000273 veterinary drug Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- UQBOJOOOTLPNST-UHFFFAOYSA-N Dehydroalanine Chemical compound NC(=C)C(O)=O UQBOJOOOTLPNST-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000008153 Peptide Elongation Factor Tu Human genes 0.000 description 1
- 108010049977 Peptide Elongation Factor Tu Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002070 germicidal effect Effects 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
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- 238000013519 translation Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention discloses a method for producing polypeptide antibiotics nosiheptide through fermentation. The method comprises the following steps of: inoculating streptomyces actuosus to a slant culture medium for carrying out slant culture; inoculating an obtained slant with spores to a seed bottle to culture a seed solution; inoculating the seed solution to a fermentation culture medium for carrying out fermentation culture according to an inoculation quantity of 10 wt%; and further treating the fermented fermentation liquor to obtain nosiheptide crystals. The nosiheptide is produced by adopting a fermentation method. The method is simple and easy and is low in production cost. The polypeptide antibiotics nosiheptide produced by adopting the method can be used as a safe, high-efficiency and environmental-friendly novel feed additive.
Description
Technical field
What the present invention relates to is a kind of method of fermentative Production polypeptide antibiotics nosiheptide, belongs to industrial microbial technology, fermentation engineering, pharmaceutical engineering field.
Background technology
Nosiheptide claims again nosiheptide, is a kind of new green environment protection fodder additives, is the animal specific microbiotic, be by S.actuosus (
Streptomyces actuosus) Thiopeptide antibiotics of fermentative production.Gram-positive microorganism is had very strong restraining effect, and the growth by the elongation factor Tu in the inhibition translation process and G suppress gram-positive microorganism also suppresses guanosine three, four phosphoric acid Enzyme Productions simultaneously.Nosiheptide is a kind of yellow or yellow-green colour crystallization, is insoluble in water, and fusing point 310-320 ℃, molecular formula is C
51H
43N
13O
12S
6, elementary composition is C:49.6%, H:4.0%, N:14.4%, O:16.7%, S:15.8%.Its molecular structure is comprised of five thiazole rings or reduction thiazole ring, a pyridine ring, an indole ring, a Threonine and a L-glutamic acid, and side chain is a dehydroalanine.
Nosiheptide is identified a kind of novel non-absorptive-type fodder additives, satisfies eight requirements that new feeding antibiotic is proposed, that is: 1, animal specific; 2, only has bacteriostatic action and without germicidal action; 3, effective to gram-positive microorganism; 4, do not produce by R
-The caused resistance of plasmid; 5, there is obvious promotion fowl dirty swine to produce and improve the effect of efficiency of feed utilization; 6, not digested road absorbs, the noresidue problem; 7, animal is particularly wanted high to people's security; 8, little to environmental influence.Therefore North America, France, Japan and other countries have been developed as nosiheptide the animal microbiotic, are used for fodder additives.
1988, Shanghai Medical Univ obtained the Ministry of Agriculture in June, 1998 and issues the new veterinary drug certificate of nosiheptide (three classes) (bulk drug and pre-mixture) the nosiheptide research of setting up the project.And the detection to the nosiheptide sample through China Veterinary Drugs Supervisory Inst., quality product and same kind of products at abroad always, at present nosiheptide has been widely used in China's feed industry.But the relatively external producer of China's nosiheptide fermentation yield level is on the low side, affects economic benefit.
Summary of the invention
The purpose of this invention is to provide a kind of method of fermentative Production polypeptide antibiotics nosiheptide, technological process is simple, and production cost is low, and product maintains vigour, and tiring is difficult for falling.
A kind of method of fermentative Production polypeptide antibiotics nosiheptide, technical scheme is as follows:
(1) slant culture: will receive at Beijing North and create the CPCC600041-vigor streptomycete that connection Bioteknologisk Institut buys, the bacterial strain deposit number is CPCC 600041, is inoculated in the nutritional medium, carries out slant culture, obtains sporogenic inclined-plane;
(2) seed culture: slant pore is inoculated in the seed culture medium, carries out seed culture, obtain seed liquor, the solid content of seed liquor accounts for the 20-30% of seed liquor total amount;
(3) fermentation culture: seed liquor is inoculated in the fermention medium by 10% inoculum size, carries out fermentation culture.Fermentation obtains the brown fermented liquid, carry out pre-treatment after, mycelium obtains the nosiheptide sterling with alcohol and n-butanol extraction after filtering.
Wherein during slant culture, inclined-plane nutritional medium moiety is g/L: glucose 30.0-40.0, peptone 5.0-10.0, (NH
4)
2SO
40.5-1.0, CaCO
33.0-5.0, agar 20.0-30.0; Medium pH 7.1-7.3, culture temperature 25-32 ℃, culture cycle 6-10 days.
Wherein during seed culture, the physiological saline with 0.9% is made spore suspension with the spore of cultivating on the inclined-plane, is inoculated in the 50ml seed culture medium, the seed culture medium moiety is g/L: corn steep liquor 20.0-40.0, peptone 10.0-20.0, sucrose 5.0-10.0, (NH
4)
2SO
41.0-2.0, CaCO
33.0-5.0; Medium pH 6.8-7.2, culture temperature 25-32 ℃, rotating speed 200-220rpm, amplitude 3-5cm, culture cycle 40-48h.
The fermention medium moiety is g/L: glucose 30.0-40.0, analysis for soybean powder 20.0-30.0, starch 30.0-40.0, rapeseed oil 5.0-10.0, Na
2SO
40.5-1.0, (NH
4)
2SO
41.0-2.0, NaCl 1.0-2.0, MgSO
40.3-0.5, MnSO
40.03-0.05, CaCO
33.0-5.0; Medium pH 6.8-7.2, culture temperature 25-32 ℃, rotating speed 200-250rpm, amplitude 3-5cm, culture cycle 9-10 days.
The information of CPCC600041-vigor streptomycete comes from: http://www.mum800.com/p_5/p_82805.html
Specifying information is as follows:
Platform resource number: 1511C0004000005925
The abbreviation of preservation center:
Bacterial strain deposit number: CPCC 600041
Chinese: vigor streptomycete
Generic name: Streptomyces
Plant name and add word: actuosus
The source is historical: ← Shenyang Pharmaceutical University
The collection time: 2001-01-17
The people is provided:
Separate the people:
The identifier:
Original number: 07-3759
The country of origin: China
Other preservation center numbering:
Biological hazard degree: four classes
Object causes a disease: nothing.
Streptomycete is after the nutrition slant medium is cultivated, and a large amount of canescence vegetative hyphaes are tiled in the slant culture primary surface, and aerial hyphae is white in color to little grey, and the aerial hyphae top is full of spore.
Adopt technique scheme of the present invention, according to different to the oxygen demand in the strain growth metabolic process, carry out the control by stages dissolved oxygen, this is an aerobic, the multistage integrated fermentation such as oxygen enrichment, add sodium sulfate at ferment middle, the nutritive substances such as ammonium sulfate are added the method in the source of element sulphur, and need to realize that to the difference of dissolved oxygen nosiheptide produces the enrichment culture of bacterium by the fermentation different steps, the nosiheptide height of tiring in the unit volume fermented liquid, maintain vigour for a long time, tire and be difficult for falling, adopt HPLC that the nosiheptide fermented liquid is carried out quantitative analysis, nosiheptide is tired and is reached more than the 5023 μ g/ml in the unit volume fermented liquid.
Embodiment:
Embodiment 1:
A kind of method of fermentative Production polypeptide antibiotics nosiheptide, technical scheme is as follows:
(1) slant culture: will receive at Beijing North and create the CPCC600041-vigor streptomycete that connection Bioteknologisk Institut buys, the bacterial strain deposit number is CPCC 600041, is inoculated in the nutritional medium, carries out slant culture, obtains sporogenic inclined-plane;
(2) seed culture: slant pore is inoculated in the seed culture medium, carries out seed culture, obtain seed liquor, the solid content of seed liquor accounts for 20% of seed liquor total amount;
(3) fermentation culture: seed liquor is inoculated in the fermention medium by 10% inoculum size, carries out fermentation culture.Fermentation obtains the brown fermented liquid, carry out pre-treatment after, mycelium obtains the nosiheptide sterling with alcohol and n-butanol extraction after filtering.
Wherein during slant culture, inclined-plane nutritional medium moiety is g/L: glucose 30.0, peptone 5.0, (NH
4)
2SO
40.5, CaCO
33.0, agar 20.0; Medium pH 7.1,25 ℃ of culture temperature, culture cycle 6 days.
Wherein during seed culture, the physiological saline with 0.9% is made spore suspension with the spore of cultivating on the inclined-plane, is inoculated in the 50ml seed culture medium, and the seed culture medium moiety is g/L: corn steep liquor 20.0, peptone 10.0, sucrose 5.0, (NH
4)
2SO
41.0, CaCO
33.0; Medium pH 6.8,25 ℃ of culture temperature, rotating speed 200rpm, amplitude 3cm, culture cycle 40h.
The fermention medium moiety is g/L: glucose 30.0, analysis for soybean powder 20.0, starch 30.0, rapeseed oil 5.0, Na
2SO
40.5, (NH
4)
2SO
41.0 NaCl 1.0, MgSO
40.3, MnSO
40.03, CaCO
33.0; Medium pH 6.8,25 ℃ of culture temperature, rotating speed 200-250rpm, amplitude 3-5cm, culture cycle 9 days.
Embodiment 2:
A kind of method of fermentative Production polypeptide antibiotics nosiheptide, technical scheme is as follows:
(1) slant culture: will receive at Beijing North and create the CPCC600041-vigor streptomycete that connection Bioteknologisk Institut buys, the bacterial strain deposit number is CPCC 600041, is inoculated in the nutritional medium, carries out slant culture, obtains sporogenic inclined-plane;
(2) seed culture: slant pore is inoculated in the seed culture medium, carries out seed culture, obtain seed liquor, the solid content of seed liquor accounts for 25% of seed liquor total amount;
(3) fermentation culture: seed liquor is inoculated in the fermention medium by 10% inoculum size, carries out fermentation culture.Fermentation obtains the brown fermented liquid, carry out pre-treatment after, mycelium obtains the nosiheptide sterling with alcohol and n-butanol extraction after filtering.
Wherein during slant culture, inclined-plane nutritional medium moiety is g/L: glucose 35.0, peptone 7.0, (NH
4)
2SO
40.7, CaCO
34.0, agar 25.0; Medium pH 7.2,28 ℃ of culture temperature, culture cycle 8 days.
Wherein during seed culture, the physiological saline with 0.9% is made spore suspension with the spore of cultivating on the inclined-plane, is inoculated in the 50ml seed culture medium, and the seed culture medium moiety is g/L: corn steep liquor 30.0, peptone 15.0, sucrose 7.0, (NH
4)
2SO
41.5, CaCO
34.0; Medium pH 7.0,28 ℃ of culture temperature, rotating speed 210rpm, amplitude 4cm, culture cycle 44h.
The fermention medium moiety is g/L: glucose 35.0, analysis for soybean powder 25.0, starch 35.0, rapeseed oil 7.0, Na
2SO
40.7, (NH
4)
2SO
41.5 NaCl 1.5, MgSO
40.4, MnSO
40.04, CaCO
34.0; Medium pH 7.0,28 ℃ of culture temperature, rotating speed 225rpm, amplitude 4cm, culture cycle 9.5 days.
Embodiment 3:
A kind of method of fermentative Production polypeptide antibiotics nosiheptide, technical scheme is as follows:
(1) slant culture: will receive at Beijing North and create the CPCC600041-vigor streptomycete that connection Bioteknologisk Institut buys, the bacterial strain deposit number is CPCC 600041, is inoculated in the nutritional medium, carries out slant culture, obtains sporogenic inclined-plane;
(2) seed culture: slant pore is inoculated in the seed culture medium, carries out seed culture, obtain seed liquor, the solid content of seed liquor accounts for 30% of seed liquor total amount;
(3) fermentation culture: seed liquor is inoculated in the fermention medium by 10% inoculum size, carries out fermentation culture.Fermentation obtains the brown fermented liquid, carry out pre-treatment after, mycelium obtains the nosiheptide sterling with alcohol and n-butanol extraction after filtering.
Wherein during slant culture, inclined-plane nutritional medium moiety is g/L: glucose 40.0, peptone 10.0, (NH
4)
2SO
41.0, CaCO
35.0, agar 30.0; Medium pH 7.3,32 ℃ of culture temperature, culture cycle 10 days.
Wherein during seed culture, the physiological saline with 0.9% is made spore suspension with the spore of cultivating on the inclined-plane, is inoculated in the 50ml seed culture medium, and the seed culture medium moiety is g/L: corn steep liquor 40.0, peptone 20.0, sucrose 10.0, (NH
4)
2SO
42.0, CaCO
35.0; Medium pH 7.2,32 ℃ of culture temperature, rotating speed 220rpm, amplitude 5cm, culture cycle 48h.
The fermention medium moiety is g/L: glucose 40.0, analysis for soybean powder 30.0, starch 40.0, rapeseed oil 10.0, Na
2SO
41.0, (NH
4)
2SO
42.0 NaCl 2.0, MgSO
40.5, MnSO
40.05, CaCO
35.0; Medium pH 7.2,32 ℃ of culture temperature, rotating speed 250rpm, amplitude 5cm, culture cycle 10 days.
Embodiment 4:
A kind of method of fermentative Production polypeptide antibiotics nosiheptide, technical scheme is as follows:
(1) slant culture: will receive at Beijing North and create the CPCC600041-vigor streptomycete that connection Bioteknologisk Institut buys, the bacterial strain deposit number is CPCC 600041, is inoculated in the nutritional medium, carries out slant culture, obtains sporogenic inclined-plane;
(2) seed culture: slant pore is inoculated in the seed culture medium, carries out seed culture, obtain seed liquor, the solid content of seed liquor accounts for 15% of seed liquor total amount;
(3) fermentation culture: seed liquor is inoculated in the fermention medium by 10% inoculum size, carries out fermentation culture.Fermentation obtains the brown fermented liquid, carry out pre-treatment after, mycelium obtains the nosiheptide sterling with alcohol and n-butanol extraction after filtering.
Wherein during slant culture, inclined-plane nutritional medium moiety is g/L: glucose 25.0, peptone 3.0, (NH
4)
2SO
40.3, CaCO
32.0, agar 15.0; Medium pH 7.0,20 ℃ of culture temperature, culture cycle 5 days.
Wherein during seed culture, the physiological saline with 0.9% is made spore suspension with the spore of cultivating on the inclined-plane, is inoculated in the 50ml seed culture medium, and the seed culture medium moiety is g/L: corn steep liquor 15.0, peptone 8.0, sucrose 4.0, (NH
4)
2SO
40.8, CaCO
32.0; Medium pH 6.5,20 ℃ of culture temperature, rotating speed 180rpm, amplitude 2cm, culture cycle 35h.
The fermention medium moiety is g/L: glucose 25.0-40.0, analysis for soybean powder 15.0, starch 25.0, rapeseed oil 4.0, Na
2SO
40.3, (NH
4)
2SO
40.5 NaCl 0.5, MgSO
40.2, MnSO
40.02, CaCO
32.0; Medium pH 6.5,20 ℃ of culture temperature, rotating speed 150rpm, amplitude 2cm, culture cycle 8 days.
Embodiment 5:
A kind of method of fermentative Production polypeptide antibiotics nosiheptide, technical scheme is as follows:
(1) slant culture: will receive at Beijing North and create the CPCC600041-vigor streptomycete that connection Bioteknologisk Institut buys, the bacterial strain deposit number is CPCC 600041, is inoculated in the nutritional medium, carries out slant culture, obtains sporogenic inclined-plane;
(2) seed culture: slant pore is inoculated in the seed culture medium, carries out seed culture, obtain seed liquor, the solid content of seed liquor accounts for 35% of seed liquor total amount;
(3) fermentation culture: seed liquor is inoculated in the fermention medium by 10% inoculum size, carries out fermentation culture.Fermentation obtains the brown fermented liquid, carry out pre-treatment after, mycelium obtains the nosiheptide sterling with alcohol and n-butanol extraction after filtering.
Wherein during slant culture, inclined-plane nutritional medium moiety is g/L: glucose 45.0, peptone 15.0, (NH
4)
2SO
41.5, CaCO
36.0, agar 35.0; Medium pH 7.5,35 ℃ of culture temperature, culture cycle 12 days.
Wherein during seed culture, the physiological saline with 0.9% is made spore suspension with the spore of cultivating on the inclined-plane, is inoculated in the 50ml seed culture medium, and the seed culture medium moiety is g/L: corn steep liquor 45.0, peptone 25.0, sucrose 13.0, (NH
4)
2SO
43.0, CaCO
36.0; Medium pH 7.5,35 ℃ of culture temperature, rotating speed 250rpm, amplitude 6cm, culture cycle 50h.
The fermention medium moiety is g/L: glucose 45.0, analysis for soybean powder 35.0, starch 45.0, rapeseed oil 13.0, Na
2SO
42.0, (NH
4)
2SO
44.0 NaCl 3.0, MgSO
40.8, MnSO
40.08, CaCO
38.0; Medium pH 7.5,35 ℃ of culture temperature, rotating speed 280rpm, amplitude 6cm, culture cycle 11 days.
Embodiment 6:
A kind of method of fermentative Production polypeptide antibiotics nosiheptide, technical scheme is as follows:
(1) slant culture: will receive at Beijing North and create the CPCC600041-vigor streptomycete that connection Bioteknologisk Institut buys, the bacterial strain deposit number is CPCC 600041, is inoculated in the nutritional medium, carries out slant culture, obtains sporogenic inclined-plane;
(2) seed culture: slant pore is inoculated in the seed culture medium, carries out seed culture, obtain seed liquor, the solid content of seed liquor accounts for 26% of seed liquor total amount;
(3) fermentation culture: seed liquor is inoculated in the fermention medium by 10% inoculum size, carries out fermentation culture.Fermentation obtains the brown fermented liquid, carry out pre-treatment after, mycelium obtains the nosiheptide sterling with alcohol and n-butanol extraction after filtering.
Wherein during slant culture, inclined-plane nutritional medium moiety is g/L: glucose 36.0, peptone 6.0, (NH
4)
2SO
40.9, CaCO
33.6, agar 28.0; Medium pH 7.1,30 ℃ of culture temperature, culture cycle 7 days.
Wherein during seed culture, the physiological saline with 0.9% is made spore suspension with the spore of cultivating on the inclined-plane, is inoculated in the 50ml seed culture medium, and the seed culture medium moiety is g/L: corn steep liquor 32.0, peptone 17.0, sucrose 7.0, CaCO
33.7; Medium pH 6.9,30 ℃ of culture temperature, rotating speed 205rpm, amplitude 5cm, culture cycle 45h.
The fermention medium moiety is g/L: glucose 37.0, and analysis for soybean powder 22.0, starch 37.0, rapeseed oil 8.0, NaCl 1.2, CaCO
33.8; Medium pH 7.1,30 ℃ of culture temperature, rotating speed 220rpm, amplitude 5cm, culture cycle 10 days.
Embodiment 7:
The information of CPCC600041-vigor streptomycete comes from: http://www.mum800.com/p_5/p_82805.html
Specifying information is as follows:
Platform resource number: 1511C0004000005925
The abbreviation of preservation center:
Bacterial strain deposit number: CPCC 600041
Chinese: vigor streptomycete
Generic name: Streptomyces
Plant name and add word: actuosus
The source is historical: ← Shenyang Pharmaceutical University
The collection time: 2001-01-17
The people is provided:
Separate the people:
The identifier:
Original number: 07-3759
The country of origin: China
Other preservation center numbering:
Biological hazard degree: four classes
Object causes a disease: nothing.
Streptomycete is after the nutrition slant medium is cultivated, and a large amount of canescence vegetative hyphaes are tiled in the slant culture primary surface, and aerial hyphae is white in color to little grey, and the aerial hyphae top is full of spore.
The fermented liquid that each embodiment 1-6 obtains detects with HPLC, and testing conditions is as follows:
Chromatographic column: 5 μ m, 250 * 4.6 mm Hypersil GOLD C18;
Sample size: 20 ul;
Moving phase: acetonitrile: pure water (with the phosphorus acid for adjusting pH value of 1ml85%)=50:50;
Detect wavelength: 267nm;
Temperature: 35 ℃;
Flow velocity: 1 ml/min;
The preparation of standardized solution: take by weighing 40mg nosiheptide standard substance, put in the 100ml volumetric flask,, shake up to scale with the moving phase dissolved dilution.
The processing of sample: measure the 5ml fermented liquid and place the 100ml volumetric flask, with sample extraction solvent constant volume, supersound process 30 minutes, cooling is diluted to scale with moving phase, shakes up, and filters sample introduction.The sample extraction solvent is that DMF and phosphoric acid buffer are mixed with by a certain percentage, and ratio is that nine parts of DMFs and a phosphoric acid buffer mix.
Tiring of the nosiheptide that each embodiment makes is as shown in the table:
As can be seen from the above table, it is higher that the present invention makes tiring of nosiheptide, especially the highest with tiring of embodiment 2, apparently higher than the embodiment 4 outside technique of the present invention, 5 and do not add the embodiment 6 of the nutritive substances such as sodium sulfate, ammonium sulfate, and the nosiheptide that the present invention makes tire after 30 days fall less, the embodiment 4 outer than the present invention technique, 5 and not add the embodiment 6 of the nutritive substances such as sodium sulfate, ammonium sulfate more stable, thus the present invention to make the nosiheptide productive rate high, it is strong to maintain vigour.
Claims (8)
1. the method for fermentative Production polypeptide antibiotics nosiheptide is characterized by:
Technical scheme is as follows:
(1) slant culture;
(2) seed culture;
(3) fermentation culture.
2. the method for fermentative Production polypeptide antibiotics nosiheptide is characterized by:
Technical scheme is as follows:
(1) slant culture: will receive at Beijing North and create the CPCC600041-vigor streptomycete that connection Bioteknologisk Institut buys, the bacterial strain deposit number is CPCC 600041, is inoculated in the nutritional medium, carries out slant culture, obtains sporogenic inclined-plane;
(2) seed culture: slant pore is inoculated in the seed culture medium, carries out seed culture, obtain seed liquor, the solid content of seed liquor accounts for the 20-30% of seed liquor total amount;
(3) fermentation culture: seed liquor is inoculated in the fermention medium by 10% inoculum size, carries out fermentation culture; Fermentation obtains the brown fermented liquid, carry out pre-treatment after, mycelium obtains the nosiheptide sterling with alcohol and n-butanol extraction after filtering.
3. the method for fermentative Production polypeptide antibiotics nosiheptide as claimed in claim 2, it is characterized by: during slant culture, inclined-plane nutritional medium moiety is g/L: glucose 30.0-40.0, peptone 5.0-10.0, (NH
4)
2SO
40.5-1.0, CaCO
33.0-5.0, agar 20.0-30.0; Medium pH 7.1-7.3, culture temperature 25-32 ℃, culture cycle 6-10 days.
4. the method for fermentative Production polypeptide antibiotics nosiheptide as claimed in claim 2, it is characterized by: during seed culture, physiological saline with 0.9% is made spore suspension with the spore of cultivating on the inclined-plane, be inoculated in the 50ml seed culture medium, the seed culture medium moiety is g/L: corn steep liquor 20.0-40.0, peptone 10.0-20.0, sucrose 5.0-10.0, (NH
4)
2SO
41.0-2.0, CaCO
33.0-5.0; Medium pH 6.8-7.2, culture temperature 25-32 ℃, rotating speed 200-220rpm, amplitude 3-5cm, culture cycle 40-48h.
5. the method for fermentative Production polypeptide antibiotics nosiheptide as claimed in claim 2, it is characterized by: the fermention medium moiety is g/L: glucose 30.0-40.0, analysis for soybean powder 20.0-30.0, starch 30.0-40.0, rapeseed oil 5.0-10.0, Na
2SO
40.5-1.0, (NH
4)
2SO
41.0-2.0, NaCl 1.0-2.0, MgSO
40.3-0.5, MnSO
40.03-0.05, CaCO
33.0-5.0; Medium pH 6.8-7.2, culture temperature 25-32 ℃, rotating speed 200-250rpm, amplitude 3-5cm, culture cycle 9-10 days.
6. the method for fermentative Production polypeptide antibiotics nosiheptide as claimed in claim 3, it is characterized by: during slant culture, inclined-plane nutritional medium moiety is g/L: glucose 35.0, peptone 7.0, (NH
4)
2SO
40.7, CaCO
34.0, agar 25.0; Medium pH 7.2,28 ℃ of culture temperature, culture cycle 8 days.
7. the method for fermentative Production polypeptide antibiotics nosiheptide as claimed in claim 4, it is characterized by: during seed culture, physiological saline with 0.9% is made spore suspension with the spore of cultivating on the inclined-plane, be inoculated in the 50ml seed culture medium, the seed culture medium moiety is g/L: corn steep liquor 30.0, peptone 15.0, sucrose 7.0, (NH
4)
2SO
41.5, CaCO
34.0; Medium pH 7.0,28 ℃ of culture temperature, rotating speed 210rpm, amplitude 4cm, culture cycle 44h.
8. the method for fermentative Production polypeptide antibiotics nosiheptide as claimed in claim 5, it is characterized by: the fermention medium moiety is g/L: glucose 35.0, analysis for soybean powder 25.0, starch 35.0, rapeseed oil 7.0, Na
2SO
40.7, (NH
4)
2SO
41.5 NaCl 1.5, MgSO
40.4, MnSO
40.04, CaCO
34.0; Medium pH 7.0,28 ℃ of culture temperature, rotating speed 225rpm, amplitude 4cm, culture cycle 9.5 days.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103898181A (en) * | 2014-04-17 | 2014-07-02 | 河北圣雪大成制药有限责任公司 | Method for producing nosiheptide by virtue of fermentation |
| CN104388505A (en) * | 2014-11-24 | 2015-03-04 | 苏州嘉禧萝生物科技有限公司 | Method for producing nosiheptide from active streptomyces by virtue of fermentation |
| CN104388506A (en) * | 2014-11-27 | 2015-03-04 | 苏州嘉禧萝生物科技有限公司 | Method for producing nosiheptide employing fermentation of streptomyces actuosus |
| CN104719634A (en) * | 2015-02-10 | 2015-06-24 | 河北圣雪大成制药有限责任公司 | Method for preparing nosiheptide pre-mixing agent |
| CN105695351A (en) * | 2015-12-29 | 2016-06-22 | 西藏天虹科技股份有限责任公司 | Streptomyces actuosus LB-16 and method for preparing nosiheptide from same |
| CN106319004A (en) * | 2015-07-09 | 2017-01-11 | 牡丹江佰佳信生物科技有限公司 | Fermentation culture medium capable of enhancing nosiheptide yield and culture method thereof |
| CN106319005A (en) * | 2015-07-09 | 2017-01-11 | 牡丹江佰佳信生物科技有限公司 | Fermentation culture medium capable of enhancing nosiheptide yield and culture method thereof |
| CN107868809A (en) * | 2016-09-28 | 2018-04-03 | 牡丹江佰佳信生物科技有限公司 | A kind of method and fermentation medium of fermenting and producing Nosiheptide |
| CN113151381A (en) * | 2021-04-26 | 2021-07-23 | 山东胜利生物工程有限公司 | Method for preparing nosiheptide fermentation liquor |
| CN113817623A (en) * | 2020-06-18 | 2021-12-21 | 河北圣雪大成制药有限责任公司 | Method for improving fermentation titer of nosiheptide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103898181A (en) * | 2014-04-17 | 2014-07-02 | 河北圣雪大成制药有限责任公司 | Method for producing nosiheptide by virtue of fermentation |
| CN104388505A (en) * | 2014-11-24 | 2015-03-04 | 苏州嘉禧萝生物科技有限公司 | Method for producing nosiheptide from active streptomyces by virtue of fermentation |
| CN104388506A (en) * | 2014-11-27 | 2015-03-04 | 苏州嘉禧萝生物科技有限公司 | Method for producing nosiheptide employing fermentation of streptomyces actuosus |
| CN104719634A (en) * | 2015-02-10 | 2015-06-24 | 河北圣雪大成制药有限责任公司 | Method for preparing nosiheptide pre-mixing agent |
| CN104719634B (en) * | 2015-02-10 | 2018-08-24 | 河北圣雪大成制药有限责任公司 | A method of preparing Nosiheptide premixed agent |
| CN106319005A (en) * | 2015-07-09 | 2017-01-11 | 牡丹江佰佳信生物科技有限公司 | Fermentation culture medium capable of enhancing nosiheptide yield and culture method thereof |
| CN106319004A (en) * | 2015-07-09 | 2017-01-11 | 牡丹江佰佳信生物科技有限公司 | Fermentation culture medium capable of enhancing nosiheptide yield and culture method thereof |
| CN105695351A (en) * | 2015-12-29 | 2016-06-22 | 西藏天虹科技股份有限责任公司 | Streptomyces actuosus LB-16 and method for preparing nosiheptide from same |
| CN105695351B (en) * | 2015-12-29 | 2019-04-09 | 西藏天虹科技股份有限责任公司 | S.actuosus LB-16 and the method for preparing Nosiheptide using it |
| CN107868809A (en) * | 2016-09-28 | 2018-04-03 | 牡丹江佰佳信生物科技有限公司 | A kind of method and fermentation medium of fermenting and producing Nosiheptide |
| CN107868809B (en) * | 2016-09-28 | 2021-07-13 | 牡丹江佰佳信生物科技有限公司 | Method for producing nosiheptide through fermentation and fermentation culture medium |
| CN113817623A (en) * | 2020-06-18 | 2021-12-21 | 河北圣雪大成制药有限责任公司 | Method for improving fermentation titer of nosiheptide |
| CN113817623B (en) * | 2020-06-18 | 2023-10-31 | 河北圣雪大成制药有限责任公司 | Method for improving fermentation titer of nosiheptide |
| CN113151381A (en) * | 2021-04-26 | 2021-07-23 | 山东胜利生物工程有限公司 | Method for preparing nosiheptide fermentation liquor |
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