CN108949845B - Fermentation medium and method for preparing mupirocin from fermentation medium - Google Patents
Fermentation medium and method for preparing mupirocin from fermentation medium Download PDFInfo
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- CN108949845B CN108949845B CN201810896368.9A CN201810896368A CN108949845B CN 108949845 B CN108949845 B CN 108949845B CN 201810896368 A CN201810896368 A CN 201810896368A CN 108949845 B CN108949845 B CN 108949845B
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- 238000000855 fermentation Methods 0.000 title claims abstract description 97
- 230000004151 fermentation Effects 0.000 title claims abstract description 97
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- 229960003128 mupirocin Drugs 0.000 title claims abstract description 48
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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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- General Chemical & Material Sciences (AREA)
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- Tropical Medicine & Parasitology (AREA)
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Abstract
The invention discloses a fermentation medium and a method for preparing mupirocin by the fermentation medium, wherein, firstly, fluorescent pseudomonas with good growth state, vigorous vitality and strong metabolic capability is selected, and then the fluorescent pseudomonas is activated by allocating the culture medium to prepare for selecting the best strain; then inoculating the strain to a special seed culture medium, expanding the number of excellent pseudomonas fluorescens flora, culturing to logarithmic phase to obtain seed bacterial liquid, and finally inoculating the seed bacterial liquid to the special fermentation culture medium. The culture medium provided by the invention can provide sufficient nutrition for the fluorescent pseudomonas and promote the fluorescent pseudomonas to accelerate the growth and metabolism speed, so that the mupirocin-containing fermentation liquor is obtained, and the mupirocin content in the fermentation liquor is more than 6000 ug/mL.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a fermentation medium and a method for preparing mupirocin by using the fermentation medium.
Background
Mupirocin, also known as pseudomonic acid a, is an antibiotic having growth inhibitory effects mainly on gram-positive bacteria [ such as Staphylococcus aureus (Staphylococcus aureus), Streptococcus pyogenes (Streptococcus pyogenes), Streptococcus pneumoniae (Streptococcus pneumoniae), Klebsiella pneumoniae (Klebsiella pneumoniae) ] and some gram-negative bacteria [ such as Haemophilus influenzae (Haemophilus influenzae), Neisseria gonorrhoeae (Neisseria gonorrhoeae) ] [ a.ward, d.m. campoli-Richards, Drugs 32,425-444(1986) ]. By inhibiting isoleucine-tRNA synthase, peptide synthesis of pathogenic bacteria is affected. An advantageous feature of this antibiotic is that it has very low toxicity to humans and animals and it is negative in the Ames test, mupirocin being currently used in human therapy for the treatment of skin infections (e.g. impetigo, pyoderma), nasal and external ear infections, acne, burns, eczema, psoriasis, in ulcer cases for the treatment of secondary infections, and for the prevention of nosocomial infections.
Pseudomonas fluorescens (Pseudomonas fluorescens) is known to produce mupirocin, but the fermentation level of the current preparation method is low, and the content of mupirocin in the obtained fermentation liquid is only 3000-4000 ug/ml.
Disclosure of Invention
Therefore, a fermentation culture medium which can provide sufficient nutrition for the fluorescent pseudomonas and can promote the fluorescent pseudomonas to accelerate the growth and metabolism speed is needed to be provided; meanwhile, a method for preparing mupirocin by using a fermentation medium is also provided, so that the content of mupirocin in the fermentation liquid is increased.
In order to achieve the above object, the inventors provide a fermentation medium for preparing mupirocin, which comprises the following components in percentage by weight:
the pH value of the fermentation medium is 6.0-7.0;
the growth promoter is one or a mixture of two of the following: leucine or betaine.
The fermentation medium not only contains a carbon source, but also contains components such as a nitrogen source, inorganic salt, a growth promoter and the like, so that sufficient nutrition can be provided for the fluorescent pseudomonas, the growth and metabolism speed of the fluorescent pseudomonas can be accelerated, and the content of mupirocin in the fermentation liquid is increased.
Preferably, the carbon source is one or a mixture of two or more of the following: glucose, sucrose, glycerol, soybean oil, peanut oil or starch. The carbon source provides energy required by the growth and the propagation of the thalli and carbon components required by the synthesis of the thalli.
Preferably, the nitrogen source is one or a mixture of two or more of the following: yeast powder, yeast extract, corn protein powder, soybean cake powder, peptone, semen gossypii fine powder or corn steep liquor. The nitrogen source is used for constructing thallus cell substances (amino acid, protein, nucleic acid and the like).
Preferably, the inorganic salt is one or a mixed salt of two or more of the following: ammonium, calcium, sodium, potassium, iron or phosphorus salts. The inorganic salt can constitute the cell component of thallus, act as enzyme component, enzyme activator or inhibitor, and regulate osmotic pressure, pH, oxidation-reduction potential, etc. of culture medium.
Preferably, the defoaming agent is a silicone defoaming agent. More preferably, the defoaming agent of the present invention is a commercially available product, available from Dow corporation under the trade name P-2000.
The invention also provides a method for preparing mupirocin by using the fermentation medium, which comprises the following steps:
1) screening for Pseudomonas fluorescens: selecting fluorescent pseudomonas with good growth state;
2) plate culture: inoculating the fluorescent pseudomonas obtained in the step 1) to a sterilized plate culture medium, culturing for 15-24 hours at 25-30 ℃ to obtain coated single colonies, taking 3-5 coated single colonies, dibbling 2-3 colonies each, and culturing for 15-24 hours on the plate culture medium at 25-30 ℃ to obtain dibbled single colonies;
3) slant culture: taking the dibbling single bacterial colonies obtained in the step 2), adding 1-1.5ml of sterile water into each bacterial colony, after the bacterial colonies are uniformly dispersed, taking 0.2-0.25ml of sterile water containing the dibbling single bacterial colonies, inoculating the sterile water into a slant culture medium, and culturing for 15-24 hours at the temperature of 25-30 ℃ to obtain mature slant bacterial colonies, wherein the slant culture medium and the plate culture medium in the step 2) have the same components and contents;
4) and (3) seed culture in a shaking flask: inoculating the mature inclined plane bacterial colony obtained in the step 3) into a shake flask seed culture medium, and culturing in shake flask culture equipment for 10-15h at 25-30 ℃ to obtain shake flask seed bacterial liquid;
5) seed culture: inoculating the shake flask seed bacterial liquid obtained in the step 4) to a seed culture medium, and culturing to a logarithmic phase to obtain seed bacterial liquid;
6) fermentation culture: inoculating the seed bacterial liquid cultured to the logarithmic phase in the step 5) to the fermentation medium, culturing for 60-120 hours at 25-30 ℃, and collecting the product to obtain the mupirocin-containing fermentation liquid.
In the preparation method, the fluorescent pseudomonas with good growth state, vigorous vitality and strong metabolic capability is selected firstly, and then the selected fluorescent pseudomonas is activated in a solid culture medium by preparing the culture medium to prepare for selecting the best strain; then inoculating the strain to a special seed culture medium, culturing under a proper condition, expanding the number of excellent pseudomonas fluorescens flora, culturing to a logarithmic phase to obtain a seed bacterial liquid, and finally inoculating the seed bacterial liquid to the special fermentation culture medium. The culture medium provided by the invention can provide sufficient nutrition for the fluorescent pseudomonas and promote the fluorescent pseudomonas to accelerate the growth and metabolism speed, so that the mupirocin-containing fermentation liquor is obtained, and the mupirocin content in the fermentation liquor is more than 6000 ug/mL.
Preferably, the plate culture medium of step 2) comprises the following components in percentage by weight:
0.05 to 0.2 percent of glucose;
peptone 0.5-1.5%;
0.2 to 0.8 percent of yeast powder;
0.5 to 1.5 percent of sodium chloride;
1.5 to 2.5 percent of agar powder;
the balance of water;
the pH value of the plate culture medium is 6.5-7.5. The plate culture medium can make the cultured colony appearance full.
Preferably, the shake flask seed culture medium of the step 4) comprises the following components in percentage by weight:
1-2.5% of yeast powder;
0.2 to 0.5 percent of glucose;
0.2 to 0.6 percent of disodium hydrogen phosphate;
potassium dihydrogen phosphate 0.2-0.4%;
0.01 to 0.1 percent of defoaming agent;
the balance of water;
the pH value of the shake flask seed culture medium is 6.0-7.0; the defoaming agent is an organic silicon defoaming agent. The shake flask seed culture medium can provide sufficient nutrition for strains, so that the strains are vigorous in life.
Preferably, the seed culture medium of step 5) comprises the following components in percentage by weight:
1-2.5% of yeast powder;
0.2 to 0.5 percent of glucose;
0.2 to 0.6 percent of disodium hydrogen phosphate;
potassium dihydrogen phosphate 0.2-0.4%;
0.01 to 0.1 percent of defoaming agent;
the balance of water;
the pH value of the seed culture medium is 6.0-7.0. The seed culture medium can provide sufficient nutrition for strains, so that the strains are vigorous in life.
Preferably, the fermentation medium of step 6) comprises the following components in percentage by weight:
0.2 to 0.5 percent of glucose,
2-5% of glycerol;
1-2.5% of soybean oil;
4-8% of soybean cake powder;
0.2 to 0.4 percent of ammonium sulfate;
1-2% of sodium chloride;
1-2% of anhydrous calcium chloride;
0.1 to 0.3 percent of calcium carbonate,
0.005-0.01 percent of ferric trichloride,
betaine 0.4-0.65%;
0.01 to 0.02 percent of defoaming agent;
the balance of water;
the pH value of the fermentation medium is 6.0-7.0.
The invention has the following advantages:
1. the fermentation medium can provide sufficient nutrition for the fluorescent pseudomonas and promote the fluorescent pseudomonas to accelerate the growth and metabolism speed, so that the content of mupirocin in the fermentation liquid is high.
2. The mupirocin is produced by fermentation culture under a specific microorganism strip. Different culture medium formulas and processes are adopted in the steps of plate culture, slant culture, shake flask culture, seed culture, fermentation culture and the like to achieve high yield, so that the mupirocin content in the fermentation liquor is more than 6000 ug/mL.
Detailed Description
In order to explain technical contents, structural features, and objects and effects of the technical means in detail, the following detailed description is given with reference to specific embodiments.
The invention discloses a fermentation medium for preparing mupirocin, which comprises the following components in percentage by weight:
the pH value of the fermentation medium is 6.0-7.0;
the growth promoter is one or a mixture of two of the following: leucine or betaine.
Example 1: fermentation medium
The fermentation medium of the embodiment comprises the following components in percentage by weight:
the pH value of the fermentation medium is 6.0-7.0;
example 2: fermentation medium
The fermentation medium of the embodiment comprises the following components in percentage by weight:
the pH value of the fermentation medium is 6.0-7.0.
Example 3: fermentation medium
The fermentation medium of the embodiment comprises the following components in percentage by weight:
the pH value of the fermentation medium is 6.0-7.0.
Example 4: fermentation medium
The fermentation medium of the embodiment comprises the following components in percentage by weight:
the pH value of the fermentation medium is 6.0-7.0.
Example 5: fermentation medium
The fermentation medium of the embodiment comprises the following components in percentage by weight:
the pH value of the fermentation medium is 6.0-7.0.
Example 6: fermentation medium
The fermentation medium of the embodiment comprises the following components in percentage by weight:
the pH value of the fermentation medium is 6.0-7.0.
The invention also provides a method for preparing mupirocin by using the fermentation medium, which comprises the following steps:
1) screening for Pseudomonas fluorescens: selecting fluorescent pseudomonas with good growth state;
2) plate culture: inoculating the fluorescent pseudomonas obtained in the step 1) to a sterilized plate culture medium, culturing for 15-24 hours at 25-30 ℃ to obtain coated single colonies, taking 3-5 coated single colonies, dibbling 2-3 colonies each, and culturing for 15-24 hours on the plate culture medium at 25-30 ℃ to obtain dibbled single colonies;
3) slant culture: taking the dibbling single bacterial colonies obtained in the step 2), adding 1-1.5ml of sterile water into each bacterial colony, after the bacterial colonies are uniformly dispersed, taking 0.2-0.25ml of sterile water containing the dibbling single bacterial colonies, inoculating the sterile water into a slant culture medium, and culturing for 15-24 hours at the temperature of 25-30 ℃ to obtain mature slant bacterial colonies, wherein the slant culture medium and the plate culture medium in the step 2) have the same components and contents;
4) and (3) seed culture in a shaking flask: inoculating the mature inclined plane bacterial colony obtained in the step 3) into a shake flask seed culture medium, and culturing in shake flask culture equipment for 10-15h at 25-30 ℃ to obtain shake flask seed bacterial liquid;
5) seed culture: inoculating the shake flask seed bacterial liquid obtained in the step 4) to a seed culture medium, and culturing to a logarithmic phase to obtain seed bacterial liquid;
6) fermentation culture: inoculating the seed bacterial liquid cultured to the logarithmic phase in the step 5) to the fermentation medium, culturing for 60-120 hours at 25-30 ℃, and collecting the product to obtain the mupirocin-containing fermentation liquid.
Example 7: method for preparing mupirocin from fermentation medium
1) Screening for Pseudomonas fluorescens: selecting fluorescent pseudomonas with good growth state;
2) plate culture: inoculating the fluorescent pseudomonas obtained in the step 1) to a sterilized plate culture medium, culturing for 15 hours at 25-30 ℃ to obtain coated single colonies, taking 4 coated single colonies, dibbling 3 colonies each, and culturing for 22 hours on the plate culture medium at 25-30 ℃ to obtain dibbling single colonies; the preparation method of the plate culture medium comprises the following steps:
firstly, weighing the following components in percentage by weight:
0.05% of glucose;
peptone 1.5%;
0.2% of yeast powder;
1.5 percent of sodium chloride;
1.5% of agar powder;
the balance of water;
uniformly mixing the components to obtain a mixed solution, and adjusting the pH of the mixed solution to 6.5-7.5;
thirdly, sterilizing for 20-30 minutes by adopting a high-pressure sterilization pot method at the temperature of 121-; after sterilization, cooling the mixed solution to 45-55 ℃, and pouring the plate in an aseptic environment to obtain a sterilized plate solid culture medium;
3) slant culture: taking the dibbling single bacterial colonies obtained in the step 2), adding 1ml of sterile water into each bacterial colony, after the bacterial colonies are uniformly dispersed, taking 0.25ml of sterile water containing the dibbling single bacterial colonies, inoculating the sterile water into a slant culture medium, and culturing for 15 hours at the temperature of 25-30 ℃ to obtain mature slant bacterial colonies, wherein the slant culture medium and the plate culture medium in the step 2) have the same components and contents;
4) and (3) seed culture in a shaking flask: inoculating the mature inclined plane bacterial colony obtained in the step 3) into a shake flask seed culture medium, and culturing for 11 hours in shake flask culture equipment at 25-30 ℃ to obtain shake flask seed bacterial liquid; the shake flask seed culture medium comprises the following components in percentage by weight:
2.0% of yeast powder;
0.3 percent of glucose;
0.5 percent of disodium hydrogen phosphate;
potassium dihydrogen phosphate 0.3%;
0.06% of defoaming agent;
the balance of water;
5) seed culture: inoculating the shake flask seed bacterial liquid obtained in the step 4) to a seed culture medium, and culturing to a logarithmic phase to obtain seed bacterial liquid; the seed culture medium comprises the following components in percentage by weight:
1.5 percent of yeast powder;
0.3 percent of glucose;
0.5 percent of disodium hydrogen phosphate;
potassium dihydrogen phosphate 0.3%;
0.08 percent of defoaming agent;
the balance of water;
the pH value of the seed culture medium is 6.0-7.0.
6) Fermentation culture: inoculating the seed bacterial liquid cultured to the logarithmic phase in the step 5) to the fermentation medium prepared in the example 1, culturing for 60 hours at 25-30 ℃, and collecting the product to obtain the mupirocin-containing fermentation liquid. Through detection, the mupirocin content in the fermentation liquor is 6000 ug/mL.
Example 8: method for preparing mupirocin from fermentation medium
1) Screening for Pseudomonas fluorescens: selecting fluorescent pseudomonas with good growth state;
2) plate culture: inoculating the fluorescent pseudomonas obtained in the step 1) to a sterilized plate culture medium, culturing for 15 hours at 25-30 ℃ to obtain coated single colonies, taking 3 coated single colonies, dibbling 3 colonies each, and culturing for 24 hours on the plate culture medium at 25-30 ℃ to obtain dibbled single colonies; the preparation method of the plate culture medium comprises the following steps:
firstly, weighing the following components in percentage by weight:
0.2% of glucose;
0.5% of peptone;
0.8 percent of yeast powder;
0.5 percent of sodium chloride;
2.5 percent of agar powder;
the balance of water;
uniformly mixing the components to obtain a mixed solution, and adjusting the pH of the mixed solution to 6.5-7.5;
thirdly, sterilizing for 20-30 minutes by adopting a high-pressure sterilization pot method at the temperature of 121-; after sterilization, cooling the mixed solution to 45-55 ℃, and pouring the plate in an aseptic environment to obtain a sterilized plate solid culture medium;
3) slant culture: taking the dibbling single bacterial colonies obtained in the step 2), adding 1.5ml of sterile water into each bacterial colony, after the bacterial colonies are uniformly dispersed, taking 0.2ml of sterile water containing the dibbling single bacterial colonies, inoculating the sterile water into a slant culture medium, and culturing for 24 hours at the temperature of 25-30 ℃ to obtain mature slant bacterial colonies, wherein the slant culture medium has the same components and content as the plate culture medium in the step 2);
4) and (3) seed culture in a shaking flask: inoculating the mature inclined plane bacterial colony obtained in the step 3) into a shake flask seed culture medium, and culturing for 14 hours in shake flask culture equipment at 25-30 ℃ to obtain shake flask seed bacterial liquid; the shake flask seed culture medium comprises the following components in percentage by weight:
15% of yeast powder;
0.4 percent of glucose;
0.4 percent of disodium hydrogen phosphate;
potassium dihydrogen phosphate 0.3%;
0.05% of defoaming agent;
the balance of water;
5) seed culture: inoculating the shake flask seed bacterial liquid obtained in the step 4) to a seed culture medium, and culturing to a logarithmic phase to obtain seed bacterial liquid; the seed culture medium comprises the following components in percentage by weight:
1% of yeast powder;
0.5 percent of glucose;
0.2 percent of disodium hydrogen phosphate;
potassium dihydrogen phosphate 0.4%;
0.01 percent of defoaming agent;
the balance of water;
the pH value of the seed culture medium is 6.0-7.0.
6) Fermentation culture: inoculating the seed bacterial liquid cultured to the logarithmic phase in the step 5) to the fermentation medium prepared in the example 2, culturing for 120 hours at 25-30 ℃, and collecting the product to obtain the mupirocin-containing fermentation liquid. Through detection, the mupirocin content in the fermentation liquor is 6500 ug/mL.
Example 9: method for preparing mupirocin from fermentation medium
1) Screening for Pseudomonas fluorescens: selecting fluorescent pseudomonas with good growth state;
2) plate culture: inoculating the fluorescent pseudomonas obtained in the step 1) to a sterilized plate culture medium, culturing for 24 hours at 25-30 ℃ to obtain coated single colonies, taking 5 coated single colonies, dibbling 2 colonies each, and culturing for 15 hours on the plate culture medium at 25-30 ℃ to obtain dibbling single colonies; the preparation method of the plate culture medium comprises the following steps:
firstly, weighing the following components in percentage by weight:
0.1% of glucose;
peptone 1.0%;
0.4% of yeast powder;
1.0% of sodium chloride;
2.0% of agar powder;
the balance of water;
uniformly mixing the components to obtain a mixed solution, and adjusting the pH of the mixed solution to 6.5-7.5;
thirdly, sterilizing for 20-30 minutes by adopting a high-pressure sterilization pot method at the temperature of 121-; after sterilization, cooling the mixed solution to 45-55 ℃, and pouring the plate in an aseptic environment to obtain a sterilized plate solid culture medium;
3) slant culture: taking the dibbling single bacterial colonies obtained in the step 2), adding 1.3ml of sterile water into each bacterial colony, after the bacterial colonies are uniformly dispersed, taking 0.22ml of sterile water containing the dibbling single bacterial colonies, inoculating the sterile water into a slant culture medium, and culturing for 22 hours at the temperature of 25-30 ℃ to obtain mature slant bacterial colonies, wherein the slant culture medium has the same components and content as the plate culture medium in the step 2);
4) and (3) seed culture in a shaking flask: inoculating the mature inclined plane bacterial colony obtained in the step 3) into a shake flask seed culture medium, and culturing for 15h in shake flask culture equipment at 25-30 ℃ to obtain shake flask seed bacterial liquid; the shake flask seed culture medium comprises the following components in percentage by weight:
2.5 percent of yeast powder;
0.2% of glucose;
0.6 percent of disodium hydrogen phosphate;
potassium dihydrogen phosphate 0.2%;
0.1% of defoaming agent;
the balance of water;
5) seed culture: inoculating the shake flask seed bacterial liquid obtained in the step 4) to a seed culture medium, and culturing to a logarithmic phase to obtain seed bacterial liquid; the seed culture medium comprises the following components in percentage by weight:
2.5 percent of yeast powder;
0.2% of glucose;
0.6 percent of disodium hydrogen phosphate;
potassium dihydrogen phosphate 0.2%;
0.1% of defoaming agent;
the balance of water;
the pH value of the seed culture medium is 6.0-7.0.
6) Fermentation culture: inoculating the seed bacterial liquid cultured to the logarithmic phase in the step 5) to the fermentation medium prepared in the embodiment 3, culturing for 80 hours at 25-30 ℃, and collecting the product to obtain the mupirocin-containing fermentation liquid. Through detection, the mupirocin content in the fermentation liquor is 6600 ug/mL.
Example 10: method for preparing mupirocin from fermentation medium
1) Screening for Pseudomonas fluorescens: selecting fluorescent pseudomonas with good growth state;
2) plate culture: inoculating the fluorescent pseudomonas obtained in the step 1) to a sterilized plate culture medium, culturing for 20 hours at 25-30 ℃ to obtain coated single colonies, taking 4 coated single colonies, dibbling 2 colonies each, and culturing for 21 hours on the plate culture medium at 25-30 ℃ to obtain dibbling single colonies; the preparation method of the plate culture medium comprises the following steps:
firstly, weighing the following components in percentage by weight:
0.15 percent of glucose;
0.8% of peptone;
0.6 percent of yeast powder;
1.2 percent of sodium chloride;
2.3 percent of agar powder;
the balance of water;
uniformly mixing the components to obtain a mixed solution, and adjusting the pH of the mixed solution to 6.5-7.5;
thirdly, sterilizing for 20-30 minutes by adopting a high-pressure sterilization pot method at the temperature of 121-; after sterilization, cooling the mixed solution to 45-55 ℃, and pouring the plate in an aseptic environment to obtain a sterilized plate solid culture medium;
3) slant culture: taking the dibbling single bacterial colonies obtained in the step 2), adding 1.3ml of sterile water into each bacterial colony, after the bacterial colonies are uniformly dispersed, taking 0.24ml of sterile water containing the dibbling single bacterial colonies, inoculating the sterile water into a slant culture medium, and culturing for 18 hours at the temperature of 25-30 ℃ to obtain mature slant bacterial colonies, wherein the slant culture medium has the same components and content as the plate culture medium in the step 2);
4) and (3) seed culture in a shaking flask: inoculating the mature inclined plane bacterial colony obtained in the step 3) into a shake flask seed culture medium, and culturing in shake flask culture equipment for 10 hours at 25-30 ℃ to obtain shake flask seed bacterial liquid; the shake flask seed culture medium comprises the following components in percentage by weight:
1% of yeast powder;
0.5 percent of glucose;
0.2 percent of disodium hydrogen phosphate;
potassium dihydrogen phosphate 0.4%;
0.01 percent of defoaming agent;
the balance of water;
5) seed culture: inoculating the shake flask seed bacterial liquid obtained in the step 4) to a seed culture medium, and culturing to a logarithmic phase to obtain seed bacterial liquid; the seed culture medium comprises the following components in percentage by weight:
2.0% of yeast powder;
0.4 percent of glucose;
0.5 percent of disodium hydrogen phosphate;
potassium dihydrogen phosphate 0.3%;
0.07 percent of defoaming agent;
the balance of water;
the pH value of the seed culture medium is 6.0-7.0.
6) Fermentation culture: inoculating the seed bacterial liquid cultured to the logarithmic phase in the step 5) to the fermentation medium prepared in the embodiment 4, culturing for 100 hours at 25-30 ℃, and collecting the product to obtain the mupirocin-containing fermentation liquid. Through detection, the mupirocin content in the fermentation liquor is 6300 ug/mL.
Example 11: method for preparing mupirocin from fermentation medium
In this example, the fermentation medium prepared in example 5 was used in step 6), and the other experimental conditions were the same as those in example 13. The obtained fermentation liquor is detected, and the mupirocin content in the fermentation liquor is 6200 ug/mL.
Example 12: method for preparing mupirocin from fermentation medium
In this example, the fermentation medium prepared in example 6 was used in step 6), and the other experimental conditions were the same as those in example 13. The obtained fermentation liquor is detected, and the mupirocin content in the fermentation liquor is 6000 ug/mL.
From examples 7-12, it can be seen that the fermentation medium of the present invention can provide sufficient nutrition for pseudomonas fluorescens, and can promote the pseudomonas fluorescens to accelerate the growth and metabolism speed, so that the mupirocin content in the fermentation broth is above 6000 ug/mL.
It should be noted that, although the above embodiments have been described herein, the invention is not limited thereto. Therefore, based on the innovative concepts of the present invention, the technical solutions of the present invention can be directly or indirectly applied to other related technical fields by making changes and modifications to the embodiments described herein or by using equivalent structures or equivalent processes performed in the present specification, and are included in the scope of the present invention.
Claims (6)
1. A fermentation medium for the preparation of mupirocin which is characterized in that: the fermentation medium comprises the following components in percentage by weight:
3.2 to 8 percent of carbon source;
4-8% of nitrogen source;
2.305 to 4.71 percent of inorganic salt;
0.4 to 0.65 percent of growth promoter;
0.01 to 0.02 percent of antifoaming agent;
the balance of water;
the pH value of the fermentation medium is 6.0-7.0;
the growth promoter is as follows: betaine, or betaine and leucine; the defoaming agent is an organic silicon defoaming agent;
the carbon source is one or a mixture of more than two of the following carbon sources: glucose, sucrose, glycerol, soybean oil, peanut oil or starch;
the nitrogen source is one or a mixture of more than two of the following substances: yeast powder, yeast extract, corn protein powder, soybean cake powder, peptone, semen gossypii fine powder or corn steep liquor;
the inorganic salt is one or more mixed salts of the following: ammonium, calcium, sodium, potassium, iron or phosphorus salts.
2. A process for the preparation of mupirocin using the fermentation medium of claim 1 wherein: which comprises the following steps:
1) screening for Pseudomonas fluorescens: selecting fluorescent pseudomonas with good growth state; 2) plate culture: inoculating the fluorescent pseudomonas obtained in the step 1) to a sterilized plate culture medium, culturing for 15-24 hours at 25-30 ℃ to obtain coated single colonies, taking 3-5 coated single colonies, dibbling 2-3 colonies each, and culturing for 15-24 hours on the plate culture medium at 25-30 ℃ to obtain dibbled single colonies;
3) slant culture: taking the dibbling single bacterial colonies obtained in the step 2), adding 1-1.5ml of sterile water into each bacterial colony, after the bacterial colonies are uniformly dispersed, taking 0.2-0.25ml of sterile water containing the dibbling single bacterial colonies, inoculating the sterile water into a slant culture medium, and culturing for 15-24 hours at the temperature of 25-30 ℃ to obtain mature slant bacterial colonies, wherein the slant culture medium and the plate culture medium in the step 2) have the same components and contents; 4) and (3) seed culture in a shaking flask: inoculating the mature inclined plane bacterial colony obtained in the step 3) into a shake flask seed culture medium, and culturing in shake flask culture equipment for 10-15h at 25-30 ℃ to obtain shake flask seed bacterial liquid; 5) seed culture: inoculating the shake flask seed bacterial liquid obtained in the step 4) to a seed culture medium, and culturing to a logarithmic phase to obtain seed bacterial liquid; 6) fermentation culture: inoculating the seed bacterial liquid cultured to the logarithmic phase in the step 5) to the fermentation medium of claim 1, culturing for 60-120 hours at 25-30 ℃, and collecting the product to obtain the mupirocin-containing fermentation liquid.
3. A process for the preparation of mupirocin according to claim 2 wherein: the plate culture medium in the step 2) comprises the following components in percentage by weight:
0.05 to 0.2 percent of glucose; peptone 0.5-1.5%; 0.2 to 0.8 percent of yeast powder; 0.5 to 1.5 percent of sodium chloride;
1.5 to 2.5 percent of agar powder;
the balance of water;
the pH value of the plate culture medium is 6.5-7.5.
4. A process for the preparation of mupirocin according to claim 2 wherein: the shake flask seed culture medium of the step 4) comprises the following components in percentage by weight: 1-2.5% of yeast powder; 0.2 to 0.5 percent of glucose; 0.2 to 0.6 percent of disodium hydrogen phosphate; potassium dihydrogen phosphate 0.2-0.4%; 0.01 to 0.1 percent of defoaming agent; the balance of water; the pH value of the shake flask seed culture medium is 6.0-7.0; the defoaming agent is an organic silicon defoaming agent.
5. A process for the preparation of mupirocin according to claim 2 wherein: the seed culture medium of the step 5) comprises the following components in percentage by weight: 1-2.5% of yeast powder; 0.2 to 0.5 percent of glucose; 0.2 to 0.6 percent of disodium hydrogen phosphate; potassium dihydrogen phosphate 0.2-0.4%; 0.01 to 0.1 percent of defoaming agent; the balance of water; the pH value of the seed culture medium is 6.0-7.0.
6. A process for the preparation of mupirocin according to claim 2 wherein: the fermentation medium in the step 6) comprises the following components in percentage by weight:
0.2 to 0.5 percent of glucose; 2-5% of glycerol;
1-2.5% of soybean oil;
4-8% of soybean cake powder; 0.2 to 0.4 percent of ammonium sulfate; 1-2% of sodium chloride; 1-2% of anhydrous calcium chloride; 0.1 to 0.3 percent of calcium carbonate; 0.005-0.01% of ferric trichloride; betaine 0.4-0.65%;
0.01 to 0.02 percent of defoaming agent; the balance of water; the pH value of the fermentation medium is 6.0-7.0.
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| CN111996136A (en) * | 2020-07-24 | 2020-11-27 | 北大方正集团有限公司 | Pseudomonas fluorescens fermentation medium, culture method and application |
| US20240043888A1 (en) * | 2021-02-07 | 2024-02-08 | Hangzhou Zhongmeihuadong Pharmaceutical Co., Ltd. | Fermentation method for mupirocin |
| CN113274346A (en) * | 2021-05-25 | 2021-08-20 | 满孝勇 | Application of mupirocin ointment |
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Granted publication date: 20210810 Pledgee: Fujian Straits bank Limited by Share Ltd. Fuqing branch Pledgor: FUJIAN KANGHONG BIOTECHNOLOGY Co.,Ltd. Registration number: Y2023350000121 |
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Denomination of invention: A fermentation medium and a method for preparing mupirocin from fermentation medium Granted publication date: 20210810 Pledgee: Fujian Straits bank Limited by Share Ltd. Fuqing branch Pledgor: FUJIAN KANGHONG BIOTECHNOLOGY Co.,Ltd. Registration number: Y2024350000040 |
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