CN108949845A - A kind of fermentation medium and the method that mupirocin is prepared by fermentation medium - Google Patents
A kind of fermentation medium and the method that mupirocin is prepared by fermentation medium Download PDFInfo
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- CN108949845A CN108949845A CN201810896368.9A CN201810896368A CN108949845A CN 108949845 A CN108949845 A CN 108949845A CN 201810896368 A CN201810896368 A CN 201810896368A CN 108949845 A CN108949845 A CN 108949845A
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- mupirocin
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- 238000000855 fermentation Methods 0.000 title claims abstract description 89
- 230000004151 fermentation Effects 0.000 title claims abstract description 89
- MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Natural products CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229960003128 mupirocin Drugs 0.000 title claims abstract description 47
- 229930187697 mupirocin Natural products 0.000 title claims abstract description 47
- DDHVILIIHBIMQU-YJGQQKNPSA-L mupirocin calcium hydrate Chemical compound O.O.[Ca+2].C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1.C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1 DDHVILIIHBIMQU-YJGQQKNPSA-L 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 25
- 239000002609 medium Substances 0.000 claims abstract description 109
- 238000011218 seed culture Methods 0.000 claims abstract description 52
- 239000001963 growth medium Substances 0.000 claims abstract description 48
- 241000894006 Bacteria Species 0.000 claims abstract description 43
- 241000589540 Pseudomonas fluorescens Species 0.000 claims abstract description 38
- 239000007788 liquid Substances 0.000 claims abstract description 29
- 230000012010 growth Effects 0.000 claims abstract description 16
- 239000000843 powder Substances 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 238000007747 plating Methods 0.000 claims description 30
- 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 22
- 239000008103 glucose Substances 0.000 claims description 22
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 20
- 239000002518 antifoaming agent Substances 0.000 claims description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 230000003698 anagen phase Effects 0.000 claims description 14
- 239000011248 coating agent Substances 0.000 claims description 14
- 238000000576 coating method Methods 0.000 claims description 14
- 239000008223 sterile water Substances 0.000 claims description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 12
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 12
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 12
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 244000068988 Glycine max Species 0.000 claims description 8
- 235000010469 Glycine max Nutrition 0.000 claims description 8
- 239000001888 Peptone Substances 0.000 claims description 8
- 108010080698 Peptones Proteins 0.000 claims description 8
- 235000019319 peptone Nutrition 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- 238000011081 inoculation Methods 0.000 claims description 7
- 230000035800 maturation Effects 0.000 claims description 7
- 229920001817 Agar Polymers 0.000 claims description 6
- 239000008272 agar Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 229960003237 betaine Drugs 0.000 claims description 5
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000013530 defoamer Substances 0.000 claims description 4
- 239000007952 growth promoter Substances 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000003921 oil Substances 0.000 claims description 4
- 235000019198 oils Nutrition 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 239000010703 silicon Substances 0.000 claims description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 3
- 240000008042 Zea mays Species 0.000 claims description 3
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 235000005822 corn Nutrition 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 229920000742 Cotton Polymers 0.000 claims description 2
- 235000019483 Peanut oil Nutrition 0.000 claims description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- 229940041514 candida albicans extract Drugs 0.000 claims description 2
- CUXQLKLUPGTTKL-UHFFFAOYSA-M microcosmic salt Chemical compound [NH4+].[Na+].OP([O-])([O-])=O CUXQLKLUPGTTKL-UHFFFAOYSA-M 0.000 claims description 2
- 239000000312 peanut oil Substances 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000012138 yeast extract Substances 0.000 claims description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims 1
- 239000001103 potassium chloride Substances 0.000 claims 1
- 235000011164 potassium chloride Nutrition 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 claims 1
- 235000016709 nutrition Nutrition 0.000 abstract description 8
- 230000035764 nutrition Effects 0.000 abstract description 8
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- 230000002503 metabolic effect Effects 0.000 abstract description 2
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- 210000001082 somatic cell Anatomy 0.000 description 2
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- MINDHVHHQZYEEK-HBBNESRFSA-N mupirocin Chemical compound C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-HBBNESRFSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
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- 206010033072 otitis externa Diseases 0.000 description 1
- 230000033116 oxidation-reduction process Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- 231100000397 ulcer Toxicity 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
- C12P17/162—Heterorings having oxygen atoms as the only ring heteroatoms, e.g. Lasalocid
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
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- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
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- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
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- Tropical Medicine & Parasitology (AREA)
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Abstract
A kind of method that the present invention discloses fermentation medium and prepares mupirocin by fermentation medium, it is good that growth conditions are selected first, vitality is vigorous, the strong Pseudomonas fluorescence of metabolic capability, then pass through allotment culture medium, Pseudomonas fluorescence carries out actication of culture, prepares to select optimal strain；Then by being inoculated on special seed culture medium, expand the Microflora of excellent Pseudomonas fluorescence, cultivate to logarithmic phase, obtain seed bacterium solution, be finally seeded to seed bacterium solution on special fermentation medium.Culture medium provided by the invention can either provide sufficient nutrition for Pseudomonas fluorescence, and Pseudomonas fluorescence can be promoted to accelerate growth metabolism speed, to obtain the fermentation liquid containing mupirocin, mupirocin content is 6000ug/mL or more in fermentation liquid.
Description
Technical field
Mupirocin is prepared the present invention relates to drug field more particularly to a kind of fermentation medium and by fermentation medium
Method.
Background technique
Mupirocin, also referred to as Pseudomonic Acid A are a kind of mainly to gram-positive bacteria [such as staphylococcus aureus
(Staphylococcus aureus), streptococcus pyogenes (Streptococcus pyogenes), streptococcus pneumonia
(Streptococcus pneumoniae), klebsiella pneumoniae (Klebsiella pneumoniae)] and some gram-negatives
Property bacterium [such as haemophilus influenzae (Haemophilus influenzae), Diplococcus gonorrhoeae (Neisseria
Gonorrhoeae)] with growth inhibition effect antibiotic [A.Ward, D.M.Campoli-Richards, Drugs 32,
425-444(1986)].By inhibiting isoleucine-tRNA synthase, the peptide synthesis of pathogen is influenced.One of the antibiotic has
Benefit is characterized in that it has low-down toxicity to humans and animals and it is negative, not sieve at present in Ames (Ames) test
Star is chiefly used in the treatment of people, to treat skin infection (such as impetigo, pyoderma), nose and external ear infection, acne, burn, wet
Rash, psoriasis are used to treat superinfection in ulcer situation, and for preventing nosocomial infection.
Known Pseudomonas fluorescens (Pseudomonas fluorescens) can generate mupirocin, but current system
Preparation Method fermentation level is low, and the content of mupirocin is generally only 3000-4000ug/ml in obtained fermentation liquid.
Summary of the invention
For this reason, it may be necessary to which sufficient nutrition can either be provided for Pseudomonas fluorescence by providing one kind, and fluorescence can be promoted false
The fermentation medium of pseudomonas bacillus quickening growth metabolism speed；The side that mupirocin is prepared by fermentation medium is also provided simultaneously
Method improves the content of mupirocin in fermentation liquid.
To achieve the above object, a kind of fermentation medium for being used to prepare mupirocin, the fermentation are inventor provided
Culture medium includes the component of following weight percentage:
The pH value of the fermentation medium is 6.0-7.0；
The growth promoter is one of the following or two kinds of mixing: leucine or glycine betaine.
Fermentation medium of the present invention not only contains carbon source, also containing groups such as nitrogen source, inorganic salts, growth promoters
Point, sufficient nutrition can either be provided for Pseudomonas fluorescence, and Pseudomonas fluorescence can be promoted to accelerate growth metabolism speed
Degree, and then improve the content of mupirocin in fermentation liquid.
Preferably, the carbon source be one of the following or two or more mixing: Portugal's glucose, sucrose, glycerol, soya-bean oil,
Peanut oil or starch.Carbon component needed for the carbon source provides required energy and synthesis thallus for thalli growth breeding.
Preferably, the nitrogen source is one of the following or two or more mixing: yeast powder, yeast extract, zein
Powder, soybean cake powder, peptone, cotton seed fine powder or corn pulp.The nitrogen source is for constructing somatic cells substance (amino acid, albumen
Matter and nucleic acid etc.).
Preferably, the inorganic salts are one of the following or two or more mixed salt: ammonium salt, calcium salt, sodium salt, potassium
Salt, molysite or microcosmic salt.The inorganic salts may make up somatic cells composition, as the component part of enzyme, the activator of enzyme or inhibition
Agent can also adjust osmotic pressure, PH, oxidation-reduction potential of culture medium etc..
Preferably, the defomaing agent is organic silicon defoamer.It is furthermore preferred that defoaming agent of the invention is commercial product, adopt
It is purchased from company of the Dow Chemical Company, trade mark P-2000.
The present invention also provides the methods that fermentation medium described in a kind of application prepares mupirocin comprising following step
It is rapid:
1) it screens Pseudomonas fluorescence: selecting the good Pseudomonas fluorescence of growth conditions；
2) plate culture: the Pseudomonas fluorescence that step 1) is obtained is seeded on the plating medium to sterilize,
It at 25~30 DEG C, cultivates 15~24 hours, obtains coating single colonie, take coating single colonie 3-5, every dibbling 2-3,
It is cultivated 15~24 hours on 25-30 DEG C of plating medium, obtains dibbling single colonie；
3) inclined-plane culture: the dibbling single colonie for taking step 2) to obtain, every addition 1-1.5ml sterile water, wait disperse
After uniformly, the sterile water of 0.2-0.25ml single colonie containing dibbling is taken to be seeded in slant medium, at 25~30 DEG C, culture 15
~24 hours, obtain mature inclined-plane bacterium colony, the component and content of plating medium described in the slant medium and step 2)
It is all the same；
4) shake-flask seed culture: by maturation inclined-plane colony inoculation obtained in step 3) into shake-flask seed culture medium,
At 25-30 DEG C, 10-15h is cultivated in shaking flask culture device, obtains shake-flask seed bacterium solution；
5) the shake-flask seed bacterium solution that step 4) obtains seed culture: is seeded to seed culture medium, culture to logarithmic growth
Phase obtains seed bacterium solution；
6) the seed bacterium solution of culture to logarithmic growth phase in step 5) fermented and cultured: is seeded to the fermentation medium
On, it at 25-30 DEG C, cultivates 60~120 hours, collects product, obtain the fermentation liquid containing mupirocin.
In the above-mentioned preparation method of the present invention, select that growth conditions are good, and vitality is vigorous first, strong glimmering of metabolic capability
Light Pseudomonas alba carries out bacterium to select Pseudomonas fluorescence in solid medium then by allotment culture medium
Kind activation, prepares to select optimal strain；Then by being inoculated on special seed culture medium, in suitable item
It is cultivated under part, expands the Microflora of excellent Pseudomonas fluorescence, culture to logarithmic phase obtains seed bacterium solution, finally will
Seed bacterium solution is seeded on special fermentation medium.Culture medium provided by the invention can either provide for Pseudomonas fluorescence
Sufficient nutrition, and Pseudomonas fluorescence can be promoted to accelerate growth metabolism speed, to obtain the fermentation containing mupirocin
Liquid, mupirocin content is 6000ug/mL or more in fermentation liquid.
Preferably, the plating medium of the step 2) includes the component of following weight percentage:
Glucose 0.05-0.2%；
Peptone 0.5-1.5%；
Yeast powder 0.2-0.8%；
Sodium chloride 0.5-1.5%；
Agar powder 1.5-2.5%；
Surplus is water；
The pH value of the plating medium is 6.5-7.5.The plating medium can make the bacterium colony appearance cultivated full.
Preferably, the shake-flask seed culture medium of the step 4) includes the component of following weight percentage:
Yeast powder 1-2.5%；
Glucose 0.2-0.5%；
Disodium hydrogen phosphate 0.2-0.6%；
Potassium dihydrogen phosphate 0.2-0.4%；
Defoaming agent 0.01-0.1%；
Surplus is water；
The pH value of the shake-flask seed culture medium is 6.0-7.0；The defoaming agent is organic silicon defoamer.The shake-flask seed
Culture medium can provide sufficient nutrition for strain, keep strain vitality vigorous.
Preferably, the seed culture medium of the step 5) includes the component for including following weight percentage:
Yeast powder 1-2.5%；
Glucose 0.2-0.5%；
Disodium hydrogen phosphate 0.2-0.6%；
Potassium dihydrogen phosphate 0.2-0.4%；
Defoaming agent 0.01-0.1%；
Surplus is water；
The pH value of the seed culture medium is 6.0-7.0.The seed culture medium can provide sufficient nutrition for strain, make bacterium
Kind vitality is vigorous.
Preferably, the fermentation medium of the step 6) includes the component of following weight percentage:
Glucose 0.2-0.5%,
Glycerol 2-5%；
Soya-bean oil 1-2.5%；
Soybean cake powder 4-8%；
Ammonium sulfate 0.2-0.4%；
Sodium chloride 1-2%；
Anhydrous calcium chloride 1-2%；
Calcium carbonate 0.1-0.3%,
Ferric trichloride 0.005-0.01%,
Glycine betaine 0.4-0.65%；
Defoaming agent 0.01-0.02%；
Surplus is water；
The pH value of the fermentation medium is 6.0-7.0.
Advantages of the present invention is as follows:
1, fermentation medium of the invention can either provide sufficient nutrition for Pseudomonas fluorescence, and can promote fluorescence
Pseudomonas alba accelerates growth metabolism speed, to keep the content of the mupirocin of fermentation liquid high.
2, the present invention produces mupirocin by fermented and cultured under the specific item of microorganism.By in plate culture, inclined-plane training
Support, shaking flask culture, seed culture and fermented and cultured and etc. in high yield reached using different culture medium prescriptions, technique so that
Mupirocin content is 6000ug/mL or more in fermentation liquid.
Specific embodiment
Technology contents, construction feature, the objects and the effects for detailed description technical solution, below in conjunction with specific reality
Example is applied to be explained in detail.
The present invention discloses a kind of fermentation medium for being used to prepare mupirocin, and the fermentation medium includes following weight
The component of percentage composition:
The pH value of the fermentation medium is 6.0-7.0；
The growth promoter is one of the following or two kinds of mixing: leucine or glycine betaine.
Embodiment 1: fermentation medium
The fermentation medium of the present embodiment includes the component of following weight percentage:
The pH value of the fermentation medium is 6.0-7.0；
Embodiment 2: fermentation medium
The fermentation medium of the present embodiment includes the component of following weight percentage:
The pH value of the fermentation medium is 6.0-7.0.
Embodiment 3: fermentation medium
The fermentation medium of the present embodiment includes the component of following weight percentage:
The pH value of the fermentation medium is 6.0-7.0.
Embodiment 4: fermentation medium
The fermentation medium of the present embodiment includes the component of following weight percentage:
The pH value of the fermentation medium is 6.0-7.0.
Embodiment 5: fermentation medium
The fermentation medium of the present embodiment includes the component of following weight percentage:
The pH value of the fermentation medium is 6.0-7.0.
Embodiment 6: fermentation medium
The fermentation medium of the present embodiment includes the component of following weight percentage:
The pH value of the fermentation medium is 6.0-7.0.
The present invention also provides the methods that fermentation medium described in a kind of application prepares mupirocin comprising following step
It is rapid:
1) it screens Pseudomonas fluorescence: selecting the good Pseudomonas fluorescence of growth conditions；
2) plate culture: the Pseudomonas fluorescence that step 1) is obtained is seeded on the plating medium to sterilize,
It at 25~30 DEG C, cultivates 15~24 hours, obtains coating single colonie, take coating single colonie 3-5, every dibbling 2-3,
It is cultivated 15~24 hours on 25-30 DEG C of plating medium, obtains dibbling single colonie；
3) inclined-plane culture: the dibbling single colonie for taking step 2) to obtain, every addition 1-1.5ml sterile water, wait disperse
After uniformly, the sterile water of 0.2-0.25ml single colonie containing dibbling is taken to be seeded in slant medium, at 25~30 DEG C, culture 15
~24 hours, obtain mature inclined-plane bacterium colony, the component and content of plating medium described in the slant medium and step 2)
It is all the same；
4) shake-flask seed culture: by maturation inclined-plane colony inoculation obtained in step 3) into shake-flask seed culture medium,
At 25-30 DEG C, 10-15h is cultivated in shaking flask culture device, obtains shake-flask seed bacterium solution；
5) the shake-flask seed bacterium solution that step 4) obtains seed culture: is seeded to seed culture medium, culture to logarithmic growth
Phase obtains seed bacterium solution；
6) the seed bacterium solution of culture to logarithmic growth phase in step 5) fermented and cultured: is seeded to the fermentation medium
On, it at 25-30 DEG C, cultivates 60~120 hours, collects product, obtain the fermentation liquid containing mupirocin.
Embodiment 7: the method that mupirocin is prepared by fermentation medium
1) it screens Pseudomonas fluorescence: selecting the good Pseudomonas fluorescence of growth conditions；
2) plate culture: the Pseudomonas fluorescence that step 1) is obtained is seeded on the plating medium to sterilize,
It at 25~30 DEG C, cultivates 15 hours, obtains coating single colonie, take described coating single colonie 4, every dibbling 3, in 25-30
It is cultivated 22 hours on DEG C plating medium, obtains dibbling single colonie；The plating medium the preparation method is as follows:
1. first pressing weight percentage weighs component:
Glucose 0.05%；
Peptone 1.5%；
Yeast powder 0.2%；
Sodium chloride 1.5%；
Agar powder 1.5%；
Surplus is water；
2. mixing the above components evenly to obtain mixed liquor, and adjust the pH to 6.5-7.5 of mixed liquor；
3. carrying out sterilizing 20-30 minutes using high-pressure sterilizing pot method at 121-123 DEG C；After sterilizing, liquid cooling will be mixed
But to 45-55 DEG C, in gnotobasis fall plate, the plate solid medium to be sterilized；
3) inclined-plane culture: the dibbling single colonie for taking step 2) to obtain, every addition 1ml sterile water, wait be uniformly dispersed
Afterwards, it takes the sterile water of 0.25ml single colonie containing dibbling to be seeded in slant medium, at 25~30 DEG C, cultivates 15 hours, obtain
To mature inclined-plane bacterium colony, the component and content of the slant medium and plating medium described in step 2) are all the same；
4) shake-flask seed culture: by maturation inclined-plane colony inoculation obtained in step 3) into shake-flask seed culture medium,
At 25-30 DEG C, 11h is cultivated in shaking flask culture device, obtains shake-flask seed bacterium solution；The shake-flask seed culture medium includes following
The component of weight percentage:
Yeast powder 2.0%；
Glucose 0.3%；
Disodium hydrogen phosphate 0.5%；
Potassium dihydrogen phosphate 0.3%；
Defoaming agent 0.06%；
Surplus is water；
5) the shake-flask seed bacterium solution that step 4) obtains seed culture: is seeded to seed culture medium, culture to logarithmic growth
Phase obtains seed bacterium solution；The seed culture medium includes the component for including following weight percentage:
Yeast powder 1.5%；
Glucose 0.3%；
Disodium hydrogen phosphate 0.5%；
Potassium dihydrogen phosphate 0.3%；
Defoaming agent 0.08%；
Surplus is water；
The pH value of the seed culture medium is 6.0-7.0.
6) the seed bacterium solution of culture to logarithmic growth phase in step 5) fermented and cultured: is seeded to the hair of the preparation of embodiment 1
On ferment culture medium, at 25-30 DEG C, cultivates 60 hours, collect product, obtain the fermentation liquid containing mupirocin.Through detecting, institute
Stating the mupirocin content in fermentation liquid is 6000ug/mL.
Embodiment 8: the method that mupirocin is prepared by fermentation medium
1) it screens Pseudomonas fluorescence: selecting the good Pseudomonas fluorescence of growth conditions；
2) plate culture: the Pseudomonas fluorescence that step 1) is obtained is seeded on the plating medium to sterilize,
It at 25~30 DEG C, cultivates 15 hours, obtains coating single colonie, take described coating single colonie 3, every dibbling 3, in 25-30
It is cultivated 24 hours on DEG C plating medium, obtains dibbling single colonie；The plating medium the preparation method is as follows:
1. first pressing weight percentage weighs component:
Glucose 0.2%；
Peptone 0.5%；
Yeast powder 0.8%；
Sodium chloride 0.5%；
Agar powder 2.5%；
Surplus is water；
2. mixing the above components evenly to obtain mixed liquor, and adjust the pH to 6.5-7.5 of mixed liquor；
3. carrying out sterilizing 20-30 minutes using high-pressure sterilizing pot method at 121-123 DEG C；After sterilizing, liquid cooling will be mixed
But to 45-55 DEG C, in gnotobasis fall plate, the plate solid medium to be sterilized；
3) inclined-plane culture: the dibbling single colonie for taking step 2) to obtain, every addition 1.5ml sterile water, wait disperse
After even, the sterile water of 0.2ml single colonie containing dibbling is taken to be seeded in slant medium, at 25~30 DEG C, cultivates 24 hours, obtain
To mature inclined-plane bacterium colony, the slant medium is identical as the component of plating medium described in step 2) and content；
4) shake-flask seed culture: by maturation inclined-plane colony inoculation obtained in step 3) into shake-flask seed culture medium,
At 25-30 DEG C, 14h is cultivated in shaking flask culture device, obtains shake-flask seed bacterium solution；The shake-flask seed culture medium includes following
The component of weight percentage:
Yeast powder 15%；
Glucose 0.4%；
Disodium hydrogen phosphate 0.4%；
Potassium dihydrogen phosphate 0.3%；
Defoaming agent 0.05%；
Surplus is water；
5) the shake-flask seed bacterium solution that step 4) obtains seed culture: is seeded to seed culture medium, culture to logarithmic growth
Phase obtains seed bacterium solution；The seed culture medium includes the component for including following weight percentage:
Yeast powder 1%；
Glucose 0.5%；
Disodium hydrogen phosphate 0.2%；
Potassium dihydrogen phosphate 0.4%；
Defoaming agent 0.01%；
Surplus is water；
The pH value of the seed culture medium is 6.0-7.0.
6) the seed bacterium solution of culture to logarithmic growth phase in step 5) fermented and cultured: is seeded to the hair of the preparation of embodiment 2
On ferment culture medium, at 25-30 DEG C, cultivates 120 hours, collect product, obtain the fermentation liquid containing mupirocin.Through detecting,
Mupirocin content in the fermentation liquid is 6500ug/mL.
Embodiment 9: the method that mupirocin is prepared by fermentation medium
1) it screens Pseudomonas fluorescence: selecting the good Pseudomonas fluorescence of growth conditions；
2) plate culture: the Pseudomonas fluorescence that step 1) is obtained is seeded on the plating medium to sterilize,
It at 25~30 DEG C, cultivates 24 hours, obtains coating single colonie, take described coating single colonie 5, every dibbling 2, in 25-30
It is cultivated 15 hours on DEG C plating medium, obtains dibbling single colonie；The plating medium the preparation method is as follows:
1. first pressing weight percentage weighs component:
Glucose 0.1%；
Peptone 1.0%；
Yeast powder 0.4%；
Sodium chloride 1.0%；
Agar powder 2.0%；
Surplus is water；
2. mixing the above components evenly to obtain mixed liquor, and adjust the pH to 6.5-7.5 of mixed liquor；
3. carrying out sterilizing 20-30 minutes using high-pressure sterilizing pot method at 121-123 DEG C；After sterilizing, liquid cooling will be mixed
But to 45-55 DEG C, in gnotobasis fall plate, the plate solid medium to be sterilized；
3) inclined-plane culture: the dibbling single colonie for taking step 2) to obtain, every addition 1.3ml sterile water, wait disperse
After even, the sterile water of 0.22ml single colonie containing dibbling is taken to be seeded in slant medium, at 25~30 DEG C, cultivated 22 hours,
Mature inclined-plane bacterium colony is obtained, the slant medium is identical as the component of plating medium described in step 2) and content；
4) shake-flask seed culture: by maturation inclined-plane colony inoculation obtained in step 3) into shake-flask seed culture medium,
At 25-30 DEG C, 15h is cultivated in shaking flask culture device, obtains shake-flask seed bacterium solution；The shake-flask seed culture medium includes following
The component of weight percentage:
Yeast powder 2.5%；
Glucose 0.2%；
Disodium hydrogen phosphate 0.6%；
Potassium dihydrogen phosphate 0.2%；
Defoaming agent 0.1%；
Surplus is water；
5) the shake-flask seed bacterium solution that step 4) obtains seed culture: is seeded to seed culture medium, culture to logarithmic growth
Phase obtains seed bacterium solution；The seed culture medium includes the component for including following weight percentage:
Yeast powder 2.5%；
Glucose 0.2%；
Disodium hydrogen phosphate 0.6%；
Potassium dihydrogen phosphate 0.2%；
Defoaming agent 0.1%；
Surplus is water；
The pH value of the seed culture medium is 6.0-7.0.
6) the seed bacterium solution of culture to logarithmic growth phase in step 5) fermented and cultured: is seeded to the hair of the preparation of embodiment 3
On ferment culture medium, at 25-30 DEG C, cultivates 80 hours, collect product, obtain the fermentation liquid containing mupirocin.Through detecting, institute
Stating the mupirocin content in fermentation liquid is 6600ug/mL.
Embodiment 10: the method that mupirocin is prepared by fermentation medium
1) it screens Pseudomonas fluorescence: selecting the good Pseudomonas fluorescence of growth conditions；
2) plate culture: the Pseudomonas fluorescence that step 1) is obtained is seeded on the plating medium to sterilize,
It at 25~30 DEG C, cultivates 20 hours, obtains coating single colonie, take described coating single colonie 4, every dibbling 2, in 25-30
It is cultivated 21 hours on DEG C plating medium, obtains dibbling single colonie；The plating medium the preparation method is as follows:
1. first pressing weight percentage weighs component:
Glucose 0.15%；
Peptone 0.8%；
Yeast powder 0.6%；
Sodium chloride 1.2%；
Agar powder 2.3%；
Surplus is water；
2. mixing the above components evenly to obtain mixed liquor, and adjust the pH to 6.5-7.5 of mixed liquor；
3. carrying out sterilizing 20-30 minutes using high-pressure sterilizing pot method at 121-123 DEG C；After sterilizing, liquid cooling will be mixed
But to 45-55 DEG C, in gnotobasis fall plate, the plate solid medium to be sterilized；
3) inclined-plane culture: the dibbling single colonie for taking step 2) to obtain, every addition 1.3ml sterile water, wait disperse
After even, the sterile water of 0.24ml single colonie containing dibbling is taken to be seeded in slant medium, at 25~30 DEG C, cultivated 18 hours,
Mature inclined-plane bacterium colony is obtained, the slant medium is identical as the component of plating medium described in step 2) and content；
4) shake-flask seed culture: by maturation inclined-plane colony inoculation obtained in step 3) into shake-flask seed culture medium,
At 25-30 DEG C, 10h is cultivated in shaking flask culture device, obtains shake-flask seed bacterium solution；The shake-flask seed culture medium includes following
The component of weight percentage:
Yeast powder 1%；
Glucose 0.5%；
Disodium hydrogen phosphate 0.2%；
Potassium dihydrogen phosphate 0.4%；
Defoaming agent 0.01%；
Surplus is water；
5) the shake-flask seed bacterium solution that step 4) obtains seed culture: is seeded to seed culture medium, culture to logarithmic growth
Phase obtains seed bacterium solution；The seed culture medium includes the component for including following weight percentage:
Yeast powder 2.0%；
Glucose 0.4%；
Disodium hydrogen phosphate 0.5%；
Potassium dihydrogen phosphate 0.3%；
Defoaming agent 0.07%；
Surplus is water；
The pH value of the seed culture medium is 6.0-7.0.
6) the seed bacterium solution of culture to logarithmic growth phase in step 5) fermented and cultured: is seeded to the hair of the preparation of embodiment 4
On ferment culture medium, at 25-30 DEG C, cultivates 100 hours, collect product, obtain the fermentation liquid containing mupirocin.Through detecting,
Mupirocin content in the fermentation liquid is 6300ug/mL.
Embodiment 11: the method that mupirocin is prepared by fermentation medium
On the fermentation medium that in the present embodiment step 6) prepared by Application Example 5, other experiment conditions are and embodiment
13 is identical.For obtained fermentation liquid through detecting, the mupirocin content in the fermentation liquid is 6200ug/mL.
Embodiment 12: the method that mupirocin is prepared by fermentation medium
On the fermentation medium that in the present embodiment step 6) prepared by Application Example 6, other experiment conditions are and embodiment
13 is identical.For obtained fermentation liquid through detecting, the mupirocin content in the fermentation liquid is 6000ug/mL.
Can be seen that fermentation medium of the invention from embodiment 7-12 can either provide abundance for Pseudomonas fluorescence
Nutrition, and can promote Pseudomonas fluorescence accelerate growth metabolism speed, so that the content of the mupirocin of fermentation liquid be made to exist
6000ug/mL or more.
It should be noted that being not intended to limit although the various embodiments described above have been described herein
Scope of patent protection of the invention.Therefore, it based on innovative idea of the invention, change that embodiment described herein is carried out and is repaired
Change or the equivalent structure or equivalent process transformation made by using the contents of the present specification, directly or indirectly by the above technology
Scheme is used in other related technical areas, is included within scope of patent protection of the invention.
Claims (10)
1. a kind of fermentation medium for being used to prepare mupirocin, it is characterised in that: the fermentation medium includes following weight
The component of percentage composition:
The pH value of the fermentation medium is 6.0-7.0；
The growth promoter is one of the following or two kinds of mixing: leucine or glycine betaine.
2. fermentation medium according to claim 1, it is characterised in that:
The carbon source is one of the following or two or more mixing: Portugal's glucose, sucrose, glycerol, soya-bean oil, peanut oil or shallow lake
Powder.
3. fermentation medium according to claim 1, it is characterised in that: the nitrogen source be one of the following or two kinds with
On mixing: yeast powder, yeast extract, corn protein powder, soybean cake powder, peptone, cotton seed fine powder or corn pulp.
4. fermentation medium according to claim 1, it is characterised in that: the inorganic salts are one of the following or two kinds
The salt mixed above: ammonium salt, calcium salt, sodium salt, sylvite, molysite or microcosmic salt.
5. fermentation medium according to claim 1, it is characterised in that: the defomaing agent is organic silicon defoamer.
6. the method that fermentation medium described in one of application claim 1-5 prepares mupirocin, it is characterised in that: it includes
Following steps:
1) it screens Pseudomonas fluorescence: selecting the good Pseudomonas fluorescence of growth conditions；
2) plate culture: the Pseudomonas fluorescence that step 1) is obtained is seeded on the plating medium to sterilize, 25~
It at 30 DEG C, cultivates 15~24 hours, obtains coating single colonie, take coating single colonie 3-5, every dibbling 2-3,
It is cultivated 15~24 hours on 25-30 DEG C of plating medium, obtains dibbling single colonie；
3) inclined-plane culture: the dibbling single colonie for taking step 2) to obtain, every addition 1-1.5ml sterile water, wait be uniformly dispersed
Afterwards, the sterile water of 0.2-0.25ml single colonie containing dibbling is taken to be seeded in slant medium, at 25~30 DEG C, culture 15~24
Hour, mature inclined-plane bacterium colony is obtained, the component and content of the slant medium and plating medium described in step 2) are homogeneous
Together；
4) shake-flask seed culture: by maturation inclined-plane colony inoculation is into shake-flask seed culture medium obtained in step 3), in 25-30
At DEG C, 10-15h is cultivated in shaking flask culture device, obtains shake-flask seed bacterium solution；
5) seed culture: the shake-flask seed bacterium solution that step 4) obtains is seeded to seed culture medium, cultivates to logarithmic growth phase, obtains
To seed bacterium solution；
6) fermented and cultured: the seed bacterium solution of culture to logarithmic growth phase in step 5) is seeded to described in one of claim 1-5
Fermentation medium on, at 25-30 DEG C, cultivate 60~120 hours, collect product, obtain the fermentation liquid containing mupirocin.
7. the method according to claim 6 for preparing mupirocin, it is characterised in that: the plating medium of the step 2)
Component including following weight percentage:
Glucose 0.05-0.2%；
Peptone 0.5-1.5%；
Yeast powder 0.2-0.8%；
Sodium chloride 0.5-1.5%；
Agar powder 1.5-2.5%；
Surplus is water；
The pH value of the plating medium is 6.5-7.5.
8. the method according to claim 6 for preparing mupirocin, it is characterised in that: the shake-flask seed of the step 4) is trained
Feeding base includes the component of following weight percentage:
Yeast powder 1-2.5%；
Glucose 0.2-0.5%；
Disodium hydrogen phosphate 0.2-0.6%；
Potassium dihydrogen phosphate 0.2-0.4%；
Defoaming agent 0.01-0.1%；
Surplus is water；
The pH value of the shake-flask seed culture medium is 6.0-7.0；The defoaming agent is organic silicon defoamer.
9. the method according to claim 6 for preparing mupirocin, it is characterised in that: the seed culture medium of the step 5)
Including the component including following weight percentage:
Yeast powder 1-2.5%；
Glucose 0.2-0.5%；
Disodium hydrogen phosphate 0.2-0.6%；
Potassium dihydrogen phosphate 0.2-0.4%；
Defoaming agent 0.01-0.1%；
Surplus is water；
The pH value of the seed culture medium is 6.0-7.0.
10. the method according to claim 6 for preparing mupirocin, it is characterised in that: the fermented and cultured of the step 6)
Base includes the component of following weight percentage:
Glucose 0.2-0.5%；
Glycerol 2-5%；
Soya-bean oil 1-2.5%；
Soybean cake powder 4-8%；
Ammonium sulfate 0.2-0.4%；
Sodium chloride 1-2%；
Anhydrous calcium chloride 1-2%；
Calcium carbonate 0.1-0.3%；
Ferric trichloride 0.005-0.01%；
Glycine betaine 0.4-0.65%；
Defoaming agent 0.01-0.02%；
Surplus is water；
The pH value of the fermentation medium is 6.0-7.0.
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