CN106755225B - Fermentation method of pneumocandin B0 - Google Patents
Fermentation method of pneumocandin B0 Download PDFInfo
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- CN106755225B CN106755225B CN201710048503.XA CN201710048503A CN106755225B CN 106755225 B CN106755225 B CN 106755225B CN 201710048503 A CN201710048503 A CN 201710048503A CN 106755225 B CN106755225 B CN 106755225B
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- 238000000855 fermentation Methods 0.000 title claims abstract description 51
- 230000004151 fermentation Effects 0.000 title claims abstract description 51
- DQXPFAADCTZLNL-FXDJFZINSA-N pneumocandin B0 Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CC(N)=O)=CC=C(O)C=C1 DQXPFAADCTZLNL-FXDJFZINSA-N 0.000 title claims abstract description 15
- 108010016309 pneumocandin B(0) Proteins 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims abstract description 12
- 241001460671 Glarea lozoyensis Species 0.000 claims abstract description 6
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims abstract description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 30
- 229910052760 oxygen Inorganic materials 0.000 claims description 30
- 239000001301 oxygen Substances 0.000 claims description 30
- 238000009423 ventilation Methods 0.000 claims description 10
- 239000007987 MES buffer Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000007836 KH2PO4 Substances 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 4
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 4
- 239000004473 Threonine Substances 0.000 claims description 4
- 239000001963 growth medium Substances 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- WRUGWIBCXHJTDG-UHFFFAOYSA-L magnesium sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Mg+2].[O-]S([O-])(=O)=O WRUGWIBCXHJTDG-UHFFFAOYSA-L 0.000 claims description 4
- 229940061634 magnesium sulfate heptahydrate Drugs 0.000 claims description 4
- 239000002609 medium Substances 0.000 claims description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- IPMHTGKXJQHTQV-YWVCOZMLSA-N 6-(trans-4-hydroxy-l-proline)-pneumocandin bo Chemical compound C1([C@@H](O)C(O)[C@H]2C(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](O)[C@@H](O)CC(C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCCC(C)CC(C)CC)[C@H](O)CC(N)=O)=CC=C(O)C=C1 IPMHTGKXJQHTQV-YWVCOZMLSA-N 0.000 abstract description 9
- 108010070929 pneumocandin C(0) Proteins 0.000 abstract description 8
- 238000000605 extraction Methods 0.000 abstract description 2
- 238000005273 aeration Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 108010020326 Caspofungin Proteins 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229960000730 caspofungin acetate Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- BJBUEDPLEOHJGE-IMJSIDKUSA-N trans-3-hydroxy-L-proline Chemical compound O[C@H]1CC[NH2+][C@@H]1C([O-])=O BJBUEDPLEOHJGE-IMJSIDKUSA-N 0.000 description 1
- PMMYEEVYMWASQN-IMJSIDKUSA-N trans-4-Hydroxy-L-proline Natural products O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- OGUJBRYAAJYXQP-IJFZAWIJSA-N vuw370o5qe Chemical compound CC(O)=O.CC(O)=O.C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 OGUJBRYAAJYXQP-IJFZAWIJSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention provides a novel fermentation method of pneumocandin B0, which can reduce the content of pneumocandin C0 in the fermentation process and greatly reduce the cost of a downstream extraction process. The strain used in the method is Glarea lozoyensis, vitamin b5 is added in the whole fermentation process, the pH is strictly controlled, and the content of pneumocandin C0 in the fermentation liquor obtained by the method can be reduced from 6% to 1.5%.
Description
Technical Field
The invention belongs to the technical field of bioengineering, relates to microbial fermentation of antifungal medicines, and particularly relates to a microbial fermentation method of pneumocandin B0.
Background
Pneumocandin B0 is a secondary metabolite synthesized by fermentation of the mold Glarea lozoyensis. The Glaralozoyensis fermentation product has 12 analogues such as A0, B1, B2, C0, D0, E0 and the like besides a target product B0, wherein the structure of C0 is the closest to that of B0, the structural difference between the two is trans-3-hydroxyproline in B0, and trans-4-hydroxyproline in C0.
Pneumocandin B0 Cas: 135575-42-7
Pneumocandin C0 Cas: 144074-96-4
In the prior art, a resin column process is mainly adopted for purifying the pneumocandin B0, and when the column chromatography is applied to industrial production, time is consumed, the use amount of a solvent is large, the environmental pollution is easy to cause, the loss of raw materials is large, and the production cost is greatly improved. C0 is an isomer of pneumocandin B0, differing in structure by a single hydroxyl position; the C0 impurity could not be separated from pneumocandin B0 in reverse phase chromatography, only by normal phase chromatography. The C0 impurity in the fermentation broth is typically 10% and if not effectively controlled, a mixture of pneumocandin B0 and C0 is obtained. The C0 impurity can participate in the subsequent reaction, and seriously influences the quality of the caspofungin acetate.
Disclosure of Invention
In order to solve the problems, the inventor develops a new fermentation method of pneumocandin B0 through exploration, and the method can reduce the content of pneumocandin C0 in the fermentation process and greatly reduce the cost of a downstream extraction process.
The strain used in the process is Glarea lozoyensis, and the fermentation conditions are as follows:
fermentation medium (wt): 3.0% of lactose, 1.0% of threonine, 1.0% of yeast powder, 1.2% of proline and KH2PO40.15%, magnesium sulfate heptahydrate 0.05%, MES buffer salt 1.5%, pH 5.3.
The temperature is 24-26 ℃ in the fermentation process, the initial ventilation volume is 0.5-1.0 VVM, and the tank pressure is 0.04-0.06 MPa. The ventilation and the rotating speed are gradually increased in the fermentation process to ensure that the dissolved oxygen is not less than 20 percent, the rotating speed is maximum 600 r/min, and the ventilation is maximum 1.2 VVM.
After fermentation for 48 hours, vitamin b5 is added, and the addition amount is 20-40 mg/l according to the volume of the culture medium.
After fermentation for 72h (the ventilation volume and the rotating speed are adjusted to the upper limit), the pH control range is adjusted according to the change of the dissolved oxygen volume until the fermentation is finished: when the dissolved oxygen is not less than 45%, controlling the pH value to be 5.0-5.4; controlling the pH value to be 5.4-5.8 when the dissolved oxygen is 35% -45%; controlling the pH value to be 5.8-6.2 when the dissolved oxygen content is 25% -35%; when the dissolved oxygen is less than 25%, controlling the pH value to be 6.2-6.6.
The content of the pneumocandin C0 in the fermentation liquid obtained by fermentation can be reduced from 6 percent to 1.5 percent.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Fermentation strain: glarea lozoyensis
Fermentation medium (wt): 3.0% of lactose, 1.0% of threonine, 1.0% of yeast powder, 1.2% of proline and KH2PO40.15%, magnesium sulfate heptahydrate 0.05%, MES buffer salt 1.5%, pH 5.3.
Culturing in 50L fermenter, sterilizing at 121 deg.C for 30 min with 30L culture medium. The amount of the fermentation broth is 1.5L, the culture temperature of the fermentation broth is 25 ℃, the initial aeration rate is 0.9VVM, 200 revolutions and the tank pressure is 0.05Mpa, the aeration rate and the rotation speed are gradually increased in the fermentation process to ensure that the dissolved oxygen is not lower than 20 percent, the rotation speed is 600 revolutions per minute at maximum, and the aeration rate is 1.2VVM at maximum.
After fermentation for 48h, vitamin b5 was added in an amount of 30 mg/l. After fermentation for 72h (at the moment, the ventilation volume and the rotating speed are adjusted to the upper limit), the pH control range is adjusted according to the dissolved oxygen change until the fermentation is finished: when the dissolved oxygen content is not lower than 45%, controlling the pH to be 5.0-5.4, controlling the dissolved oxygen content at 96h to be 35-45%, controlling the pH to be 5.4-5.8, controlling the dissolved oxygen content at 110h to be 25-35%, controlling the pH to be 5.8-6.2, controlling the dissolved oxygen content at 130h to be lower than 25%, controlling the pH to be 6.2-6.6, controlling the dissolved oxygen content at 144h to be 25%, controlling the pH to be 5.8-6.2, controlling the dissolved oxygen content at 168h to be 35%, maintaining the dissolved oxygen content at 35-45%, controlling the pH to be 5.4-5.8, finishing fermentation at 240h, discharging a tank, and determining the fermentation unit of the pneumocandin B0 to be 1048mg/l and the content of the pneumocandin C0 to be 1.5%.
Example 2 (comparative example without addition of vitamin b 5)
Fermentation strain: glarea lozoyensis
Fermentation medium (wt): 3.0% of lactose, 1.0% of threonine, 1.0% of yeast powder, 1.2% of proline and KH2PO40.15%, magnesium sulfate heptahydrate 0.05%, MES buffer salt 1.5%, pH 5.3.
Culturing in 50L fermenter, sterilizing at 121 deg.C for 30 min with 30L culture medium. The amount of the fermentation broth is 1.5L, the culture temperature of the fermentation broth is 25 ℃, the initial aeration rate is 0.9VVM, 200 revolutions and the tank pressure is 0.05Mpa, the aeration rate and the rotation speed are gradually increased in the fermentation process to ensure that the dissolved oxygen is not lower than 20 percent, the rotation speed is 600 revolutions per minute at maximum, and the aeration rate is 1.2VVM at maximum.
After fermentation for 72h (at the moment, the ventilation volume and the rotating speed are adjusted to the upper limit), the pH control range is adjusted according to the dissolved oxygen change until the fermentation is finished: when the dissolved oxygen content is not lower than 45%, controlling the pH to be 5.0-5.4, controlling the dissolved oxygen content at 96h to be 35-45%, controlling the pH to be 5.4-5.8, controlling the dissolved oxygen content at 110h to be 25-35%, controlling the pH to be 5.8-6.2, controlling the dissolved oxygen content at 130h to be lower than 25%, controlling the pH to be 6.2-6.6, controlling the dissolved oxygen content at 144h to be increased back to 25%, controlling the pH to be 5.8-6.2, controlling the dissolved oxygen content at 168h to be increased back to 35%, maintaining the dissolved oxygen content at 35-45%, controlling the pH to be 5.4-5.8, finishing fermentation at 240h, putting a tank, and determining the fermentation unit of the pneumocandin B0 to be 1025mg/l and the content of the pneumocandin C0 to.
Claims (1)
1. A fermentation method of pneumocandin B0, wherein the strain used is Glarea lozoyensis, and the fermentation conditions of the method are as follows:
fermentation medium: 3.0 percent of lactose, 1.0 percent of threonine, 1.0 percent of yeast powder, 1.2 percent of proline and KH2PO4The mass fraction of the MES buffer salt is 0.15 percent, the mass fraction of magnesium sulfate heptahydrate is 0.05 percent, the mass fraction of MES buffer salt is 1.5 percent, and the pH value is 5.3;
the temperature is 25 ℃, the initial ventilation volume is 0.9VVM, the tank pressure is 0.05Mpa in the fermentation process, the ventilation volume and the rotating speed are gradually increased in the fermentation process to ensure that the dissolved oxygen is not less than 20 percent, the rotating speed is 600 r/min at the maximum, and the ventilation volume is 1.2VVM at the maximum;
after fermentation for 48h, vitamin b5 is added, the addition amount is 30mg/l according to the volume of the culture medium,
after fermentation is carried out for 72h, the ventilation volume and the rotating speed are adjusted to the upper limit, the pH control range is adjusted according to the change of the dissolved oxygen volume until the fermentation is finished: when the dissolved oxygen is not less than 45%, controlling the pH value to be 5.0-5.4; when the dissolved oxygen amount is 35-45%, controlling the pH value to be 5.4-5.8; when the dissolved oxygen amount is 25-35%, controlling the pH value to be 5.8-6.2; when the dissolved oxygen is less than 25%, controlling the pH value to be 6.2-6.6;
the fermentation culture period is 10 days, and the fermentation culture period is 10 days later.
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| CN201710048503.XA CN106755225B (en) | 2017-01-20 | 2017-01-20 | Fermentation method of pneumocandin B0 |
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| CN201710048503.XA CN106755225B (en) | 2017-01-20 | 2017-01-20 | Fermentation method of pneumocandin B0 |
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| CN106755225B true CN106755225B (en) | 2020-06-26 |
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| CN115747283A (en) * | 2021-09-03 | 2023-03-07 | 杭州中美华东制药有限公司 | A method for fermenting and preparing pneumocidine B0 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087928A (en) * | 2013-01-25 | 2013-05-08 | 杭州华东医药集团生物工程研究所有限公司 | The fungus Glarea lozoyensis and its application in regulating the microbial metabolite pneumocidine B0 |
| CN103289900A (en) * | 2012-02-22 | 2013-09-11 | 上海来益生物药物研究开发中心有限责任公司 | High-yield strain for pneumocandin B0 and application for same |
| CN104145021A (en) * | 2012-01-13 | 2014-11-12 | 中化帝斯曼制药有限公司荷兰公司 | Cyclopeptide fermentation at increased metal ion concentration |
-
2017
- 2017-01-20 CN CN201710048503.XA patent/CN106755225B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104145021A (en) * | 2012-01-13 | 2014-11-12 | 中化帝斯曼制药有限公司荷兰公司 | Cyclopeptide fermentation at increased metal ion concentration |
| CN103289900A (en) * | 2012-02-22 | 2013-09-11 | 上海来益生物药物研究开发中心有限责任公司 | High-yield strain for pneumocandin B0 and application for same |
| CN103087928A (en) * | 2013-01-25 | 2013-05-08 | 杭州华东医药集团生物工程研究所有限公司 | The fungus Glarea lozoyensis and its application in regulating the microbial metabolite pneumocidine B0 |
Non-Patent Citations (3)
| Title |
|---|
| Improvement in the titer of echinocandin-type antibiotics: a;Jan S.Tkacz等;《Journal of Industrial Microbiology》;19930228;第11卷(第2期);第97页左栏第4段、第100页表5及图3和第102页右栏第2段 * |
| Novel proline hydroxylase activities in the pneumocandin-producing;L.Petersen等;《Applied Microbiology and Biotechnology》;20030306;第62卷(第2期);全文 * |
| Pilot-scale process sensitivity studies for the scaleup of a fungal fermentation for the production of pneumocandins;Pollard DJ等;《Biotechnology and Bioengineering》;20020505;第78卷(第3期);第275页图5及第277页表1 * |
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