CN112410395B - Feed medium for improving fermentation titer of 6-demethyltetracycline and application thereof - Google Patents
Feed medium for improving fermentation titer of 6-demethyltetracycline and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of microbial fermentation engineering, and particularly relates to a supplemented medium for improving the fermentation titer of 6-demethyltetracycline and application thereof, wherein the supplemented medium comprises the following components in parts by weight: by mass volume ratio, 40-50% of corn starch, 0.1-0.5% of corn steep liquor, 0.1-0.2% of sodium bromide, 0.1-0.5% of L-asparagine, 0.1-0.2% of dimethyl malonate, 0.01-0.05% of cobalt chloride, 0.4% of alpha amylase (W/W of the amount of starch), 0.01-0.03% of defoaming agent and the balance of water; precursor substances for promoting the synthesis of the 6-demethyl aureomycin and metal ions for promoting synthetase are added into the feed supplement culture medium, so that the fermentation unit of the 6-demethyl aureomycin is improved, the production efficiency is improved, and the production cost is reduced.
Description
Technical Field
The invention belongs to the technical field of microbial fermentation engineering, and particularly relates to a feed supplement medium for improving the fermentation titer of 6-demethyltetracycline and application thereof.
Background
Minocycline is the one with stronger effect in tetracycline currently used, has an antibacterial spectrum similar to that of tetracycline, has very strong effect on gram-positive bacteria including tetracycline-resistant staphylococcus aureus, streptococcus and neisseria gonorrhoeae in gram-negative bacteria, and has the advantages of high efficiency, broad spectrum, low effective dose, quick oral absorption, wide in-vivo distribution, long acting effect and the like. The first step of the production process of minocycline is to take 6-demethyl aureomycin as a raw material to generate 6-demethyl tetracycline through high-pressure catalytic reaction. The 6-nortetracycline is directly obtained in large quantity by a microbial fermentation method, so that the fermentation process and the first step of high-pressure catalytic reaction of the 6-noraureomycin are reduced, the step of minocycline synthesis is simplified, the equipment investment is reduced, and the production cost is reduced.
At present, the research on producing 6-nortetracycline by fermentation in the industry is less, and the research directions mainly comprise two steps: firstly, the Streptomyces aureofaciens is transformed by the institute of microbiology of Chinese academy of sciences through the means of genetic engineering to produce 6-nortetracycline, but the shortcomings are that the production capacity of the transformed strain is low, the content of byproducts is high, and the industrialized condition is temporarily unavailable; secondly, the 6-nortetracycline is produced by fermenting streptomyces aureofaciens directly by the limited liability company of the Hebei Shengxue Dacheng pharmacy by adjusting the production process, but the fermentation titer is lower and the industrialized condition can not be achieved.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides the feed medium for improving the fermentation titer of the 6-demethyltetracycline and the application thereof, and can shorten the fermentation period of the 6-demethyltetracycline and improve the production efficiency by adjusting the components and the proportion of the fermentation medium and the feed medium; meanwhile, the fermentation tank-discharging titer of the 6-demethyltetracycline is improved, and the production cost is reduced.
The invention adopts the specific technical scheme that: a feed medium for improving the fermentation titer of 6-demethyltetracycline has the key points that: the components and the proportion of the supplementary culture medium are as follows: by mass volume ratio, 40-50% of corn starch, 0.1-0.5% of corn steep liquor, 0.1-0.2% of sodium bromide, 0.1-0.5% of L-asparagine, 0.1-0.2% of dimethyl malonate, 0.01-0.05% of cobalt chloride, 0.4% of alpha amylase (W/W of the amount of starch), 0.01-0.03% of defoaming agent and the balance of water.
The application of the feed medium for improving the fermentation titer of the 6-demethyltetracycline is characterized by comprising the following steps:
a. seed culture: inoculating the streptomycin aureus spore liquid into a seed tank filled with a seed culture medium, and culturing for 20-28h under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-;
b. fermentation culture: b, inoculating the seed solution prepared in the step a into a fermentation tank filled with a fermentation culture medium according to the inoculation amount of 20 percent of the volume ratio, and culturing under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-800rpm and the ventilation amount of 0.8-1.2 vvm;
c. feeding: preparing a material supplementing tank according to the proportion of a material supplementing culture medium, feeding material when the total sugar is reduced to 3g/100mL, controlling the content of the total sugar to be maintained at 3 +/-0.5 g/100mL, and simultaneously controlling the pH of the fermentation liquor to be within the range of 6.6-6.8 by using ammonia water;
d. and culturing for 8 days to obtain fermentation liquor, and detecting the fermentation titer of the 6-demethylated aureomycin.
Preferably, the components and the proportion of the seed culture medium in the step a are as follows: by mass volume ratio, 2.5-4.5% of corn starch, 1.5-2.5% of soybean cake powder, 0-1.0% of yeast extract powder, 1-1.5% of ammonium sulfate, 0.2-0.5% of light calcium carbonate, 0.1-0.2% of sodium bromide, 0.01-0.03% of magnesium sulfate and the balance of water.
Preferably, in the step b, the fermentation medium formula: by mass volume ratio, 4.0-6.0% of corn starch, 2.0-2.5% of soybean cake powder, 0.5-1.0% of yeast extract powder, 0.2-0.5% of ammonium sulfate, 0.5-1.0% of light calcium carbonate, 0.1-0.2% of sodium bromide, 0.01-0.03% of magnesium sulfate, 0.4% of alpha amylase (W/W of the amount of corn flour), 0.01-0.03% of defoaming agent and the balance of water.
The invention has the beneficial effects that: by researching the growth characteristics of streptomyces aureofaciens and analyzing the synthesis mechanism of 6-demethyltetracycline, firstly, the components and the proportion of the raw materials of the fermentation culture medium are adjusted, the thallus concentration is improved, the primary metabolism speed is accelerated, and on the other hand, precursor substances for promoting the synthesis of 6-demethylaureomycin and metal ions for promoting synthetase are added into the feed supplement culture medium, so that the fermentation unit of the 6-demethylaureomycin is improved by 40.52 percent, the production efficiency is improved, and the production cost is reduced.
Detailed Description
The invention provides a method for improving fermentation titer of 6-demethyltetracycline, aiming at overcoming the defects of the prior art, improving fermentation units, improving production efficiency and reducing production cost, and the invention is further explained by combining a specific embodiment as follows:
control group
a. Seed culture: inoculating the streptomycin aureus spore liquid into a seed tank filled with a seed culture medium, and culturing for 20-28h under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-;
b. fermentation culture: inoculating the seed solution prepared in the step a into a fermentation tank filled with a fermentation medium according to the inoculation amount of 20 percent of the volume ratio, and culturing under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-800rpm and the ventilation amount of 0.8-1.2 vvm.
c. Feeding: preparing a feed tank according to the feed culture medium proportion, starting feeding when the total sugar is reduced to 3g/100mL, and controlling the content of the total sugar to be maintained at 3 +/-0.5 g/100 mL. Meanwhile, ammonia water is used for controlling the pH value of the fermentation liquor within the range of 6.6-6.8.
The seed culture medium in the step a comprises the following components in proportion: calculated by mass volume ratio, the corn starch is 4 percent, the soybean cake powder is 2 percent, the yeast extract powder is 0.5 percent, the ammonium sulfate is 0.8 percent, the light calcium carbonate is 0.3 percent, the sodium bromide is 0.15 percent, the magnesium sulfate is 0.02 percent, and the rest is water.
The fermentation medium in the step b comprises the following components in proportion: the corn starch-soybean meal cake comprises, by mass volume, 5% of corn starch, 2.0% of soybean cake powder, 0.4% of ammonium sulfate, 0.8% of light calcium carbonate, 0.1% of sodium bromide, 0.02% of magnesium sulfate, 0.4% of alpha amylase (W/W of the amount of corn flour), 0.02% of a defoaming agent and the balance of water.
The components and the proportion of the feed culture medium in the step c are as follows: by mass volume ratio, the corn starch is 45%, the corn steep liquor is 0.3%, the sodium bromide is 0.1%, the alpha amylase (W/W of the starch dosage) is 0.4%, the defoaming agent is 0.02%, and the balance is water.
d. The fermentation broth is obtained after 8 days of culture, and the fermentation titer of the 6-demethyl aureomycin is 4855 mug/mL by HPLC detection.
Example 1
a. Seed culture: inoculating the streptomycin aureus spore liquid into a seed tank filled with a seed culture medium, and culturing for 20-28h under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-800rpm and the ventilation capacity of 1.0-1.5vvm to obtain a seed liquid;
b. fermentation culture: inoculating the seed solution prepared in the step a into a fermentation tank filled with a fermentation medium according to the inoculation amount of 20 percent of the volume ratio, and culturing under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-800rpm and the ventilation amount of 0.8-1.2 vvm.
c. Feeding: preparing a feed tank according to the feed culture medium proportion, starting feeding when the total sugar is reduced to 3g/100mL, and controlling the content of the total sugar to be maintained at 3 +/-0.5 g/100 mL. Meanwhile, ammonia water is used for controlling the pH value of the fermentation liquor within the range of 6.6-6.8.
The seed culture medium in the step a comprises the following components in proportion: by mass volume ratio, 4% of corn starch, 2% of soybean cake powder, 0.5% of yeast extract powder, 0.8% of ammonium sulfate, 0.3% of light calcium carbonate, 0.15% of sodium bromide, 0.02% of magnesium sulfate and the balance of water.
The fermentation medium in the step b comprises the following components in proportion: the corn starch-soybean milk powder comprises, by mass volume, 5% of corn starch, 2.0% of soybean cake powder, 0.8% of yeast extract powder, 0.4% of ammonium sulfate, 0.8% of light calcium carbonate, 0.1% of sodium bromide, 0.02% of magnesium sulfate, 0.4% of alpha amylase (W/W of the amount of corn flour), 0.02% of a defoaming agent and the balance of water.
The feed culture medium in the step c comprises the following components in proportion: the corn starch is 45 percent, the corn steep liquor is 0.3 percent, the sodium bromide is 0.1 percent, the alpha amylase (W/W of the starch dosage) is 0.4 percent, the defoaming agent is 0.02 percent, and the balance is water.
d. The fermentation broth is obtained after 8 days of culture, and the fermentation titer of the 6-demethyl aureomycin is 5103 mug/mL by HPLC detection.
Example 2
a. Seed culture: inoculating the streptomycin aureus spore liquid into a seed tank filled with a seed culture medium, and culturing for 20-28h under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-;
b. fermentation culture: inoculating the seed solution prepared in the step a into a fermentation tank filled with a fermentation medium according to the inoculation amount of 20 percent of the volume ratio, and culturing under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-800rpm and the ventilation amount of 0.8-1.2 vvm.
c. Feeding: preparing a feed tank according to the feed culture medium proportion, starting feeding when the total sugar is reduced to 3g/100mL, and controlling the content of the total sugar to be maintained at 3 +/-0.5 g/100 mL. Meanwhile, ammonia water is used for controlling the pH value of the fermentation liquor within the range of 6.6-6.8.
The seed culture medium in the step a comprises the following components in proportion: calculated by mass volume ratio, the corn starch is 4 percent, the soybean cake powder is 2 percent, the yeast extract powder is 0.5 percent, the ammonium sulfate is 0.8 percent, the light calcium carbonate is 0.3 percent, the sodium bromide is 0.15 percent, the magnesium sulfate is 0.02 percent, and the rest is water.
The fermentation medium in the step b comprises the following components in proportion: the corn starch-soybean milk powder comprises, by mass volume, 5% of corn starch, 2.0% of soybean cake powder, 0.8% of yeast extract powder, 0.4% of ammonium sulfate, 0.8% of light calcium carbonate, 0.1% of sodium bromide, 0.02% of magnesium sulfate, 0.4% of alpha amylase (W/W of the amount of corn flour), 0.02% of a defoaming agent and the balance of water.
The components and the proportion of the feed culture medium in the step c are as follows: by mass volume ratio, the corn starch accounts for 45%, the corn steep liquor accounts for 0.3%, the sodium bromide accounts for 0.1%, the L-asparagine accounts for 0.2%, the alpha amylase (W/W of the amount of the starch) accounts for 0.4%, the defoaming agent accounts for 0.02%, and the balance is water.
d. The fermentation broth is obtained after 8 days of culture, and the fermentation titer of the 6-demethyl aureomycin is 5681 mug/mL by HPLC detection.
Example 3
a. Seed culture: inoculating the streptomycin aureus spore liquid into a seed tank filled with a seed culture medium, and culturing for 20-28h under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-;
b. fermentation culture: inoculating the seed solution prepared in the step a into a fermentation tank filled with a fermentation medium according to the inoculation amount of 20 percent of the volume ratio, and culturing under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-800rpm and the ventilation amount of 0.8-1.2 vvm.
c. Feeding: preparing a feed tank according to the feed culture medium proportion, starting feeding when the total sugar is reduced to 3g/100mL, and controlling the content of the total sugar to be maintained at 3 +/-0.5 g/100 mL. Meanwhile, ammonia water is used for controlling the pH value of the fermentation liquor within the range of 6.6-6.8.
The components and the proportion of the seed culture medium in the step a are as follows: by mass volume ratio, 4% of corn starch, 2% of soybean cake powder, 0.5% of yeast extract powder, 0.8% of ammonium sulfate, 0.3% of light calcium carbonate, 0.15% of sodium bromide, 0.02% of magnesium sulfate and the balance of water.
The fermentation medium in the step b comprises the following components in percentage by weight: the corn starch-soybean milk powder comprises, by mass volume, 5% of corn starch, 2.0% of soybean cake powder, 0.8% of yeast extract powder, 0.4% of ammonium sulfate, 0.8% of light calcium carbonate, 0.1% of sodium bromide, 0.02% of magnesium sulfate, 0.4% of alpha amylase (W/W of the amount of corn flour), 0.02% of a defoaming agent and the balance of water.
The feed culture medium in the step c comprises the following components in proportion: by mass volume ratio, the corn starch is 45%, the corn steep liquor is 0.3%, the sodium bromide is 0.1%, the dimethyl malonate is 0.2%, the alpha amylase (W/W of the amount of the starch) is 0.4%, the defoaming agent is 0.02%, and the balance is water.
d. The fermentation broth is obtained after 8 days of culture, and the fermentation titer of the 6-demethyl aureomycin is 5867 mug/mL by HPLC detection.
Example 4
a. Seed culture: inoculating the streptomycin aureus spore liquid into a seed tank filled with a seed culture medium, and culturing for 20-28h under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-800rpm and the ventilation capacity of 1.0-1.5vvm to obtain a seed liquid;
b. fermentation culture: inoculating the seed solution prepared in the step a into a fermentation tank filled with a fermentation culture medium according to the inoculation amount of 20% by volume, and culturing under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-.
c. Feeding: preparing a feed tank according to the feed culture medium proportion, starting feeding when the total sugar is reduced to 3g/100mL, and controlling the content of the total sugar to be maintained at 3 +/-0.5 g/100 mL. Meanwhile, ammonia water is used for controlling the pH value of the fermentation liquor within the range of 6.6-6.8.
The components and the proportion of the seed culture medium in the step a are as follows: by mass volume ratio, 4% of corn starch, 2% of soybean cake powder, 0.5% of yeast extract powder, 0.8% of ammonium sulfate, 0.3% of light calcium carbonate, 0.15% of sodium bromide, 0.02% of magnesium sulfate and the balance of water.
The fermentation medium in the step b comprises the following components in proportion: the corn starch-soybean milk powder comprises, by mass volume, 5% of corn starch, 2.0% of soybean cake powder, 0.8% of yeast extract powder, 0.4% of ammonium sulfate, 0.8% of light calcium carbonate, 0.1% of sodium bromide, 0.02% of magnesium sulfate, 0.4% of alpha amylase (W/W of the amount of corn flour), 0.02% of a defoaming agent and the balance of water.
The components and the proportion of the feed culture medium in the step c are as follows: by mass volume ratio, the corn starch is 45%, the corn steep liquor is 0.3%, the sodium bromide is 0.1%, the cobalt chloride is 0.05%, the alpha amylase (W/W of the amount of the starch) is 0.4%, the defoaming agent is 0.02%, and the balance is water.
d. Culturing for 8 days to obtain fermentation liquor, and detecting the fermentation titer of the 6-demethyl aureomycin by HPLC to be 5404 mug/mL.
Example 5
a. Seed culture: inoculating the streptomycin aureus spore liquid into a seed tank filled with a seed culture medium, and culturing for 20-28h under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-;
b. fermentation culture: inoculating the seed solution prepared in the step a into a fermentation tank filled with a fermentation culture medium according to the inoculation amount of 20% by volume, and culturing under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-.
c. Feeding: preparing a feed tank according to the feed culture medium proportion, starting feeding when the total sugar is reduced to 3g/100mL, and controlling the content of the total sugar to be maintained at 3 +/-0.5 g/100 mL. Meanwhile, ammonia water is used for controlling the pH value of the fermentation liquor within the range of 6.6-6.8.
The seed culture medium in the step a comprises the following components in proportion: calculated by mass volume ratio, the corn starch is 4 percent, the soybean cake powder is 2 percent, the yeast extract powder is 0.5 percent, the ammonium sulfate is 0.8 percent, the light calcium carbonate is 0.3 percent, the sodium bromide is 0.15 percent, the magnesium sulfate is 0.02 percent, and the rest is water.
The fermentation medium in the step b comprises the following components in proportion: the corn starch-soybean milk powder comprises, by mass volume, 5% of corn starch, 2.0% of soybean cake powder, 0.8% of yeast extract powder, 0.4% of ammonium sulfate, 0.8% of light calcium carbonate, 0.1% of sodium bromide, 0.02% of magnesium sulfate, 0.4% of alpha amylase (W/W of the amount of corn flour), 0.02% of a defoaming agent and the balance of water.
The components and the proportion of the feed culture medium in the step c are as follows: by mass volume ratio, 45% of corn starch, 0.3% of corn steep liquor, 0.1% of sodium bromide, 0.2% of L-asparagine, 0.2% of dimethyl malonate, 0.05% of cobalt chloride, 0.4% of alpha amylase (W/W of the amount of starch), 0.02% of defoaming agent and the balance of water.
d. Culturing for 8 days to obtain fermentation liquor, and detecting the fermentation titer of the 6-demethyl aureomycin by HPLC to be 6822 mu g/mL.
Example 1 shows that the tank-placing titer can be improved by 5.1% by adding 0.8% of yeast extract powder into the fermentation medium; based on example 1, the addition of 0.2% of L-asparagine, 0.2% of dimethyl malonate and 0.05% of cobalt chloride in the following order in examples 2 to 4 can respectively improve the can-placing potency by 11.3%, 15.0% and 5.9%, which shows that the three substances have positive effects on promoting the product synthesis, and the effect of adding 0.2% of dimethyl malonate is most obvious. In example 5, when 3 substances were simultaneously added to the feed medium, the pot titer of comparative example 1 was increased by 33.7% and 40.5% compared to the control group.
The feed supplement culture medium for improving the fermentation titer of the 6-demethyltetracycline provided by the invention not only can provide sufficient carbon source and nitrogen source to maintain the titer generated by the secondary metabolism of thalli, but also provides precursor substances and metal ions for promoting the synthesis of products according to the synthesis path of the 6-demethyltetracycline, increases the metabolic flow of the synthesis of the products, enables the fermentation unit of the 6-demethyltetracycline to reach 6822 mu g/mL, improves the economic feasibility of large-scale production, and reduces the production cost.
Claims (4)
1. A feed medium for improving the fermentation titer of 6-demethyltetracycline is characterized in that: the feed medium comprises the following components in proportion: by mass volume ratio, 40-50% of corn starch, 0.1-0.5% of corn steep liquor, 0.1-0.2% of sodium bromide, 0.1-0.5% of L-asparagine, 0.1-0.2% of dimethyl malonate, 0.01-0.05% of cobalt chloride, 0.4% of alpha amylase (W/W of the amount of starch), 0.01-0.03% of defoaming agent and the balance of water.
2. The use of the feed medium for increasing the fermentation titer of 6-demethyltetracycline according to claim 1, comprising the steps of:
a. seed culture: inoculating the streptomycin aureus spore liquid into a seed tank filled with a seed culture medium, and culturing for 20-28h under the conditions of the temperature of 27-29 ℃, the rotation speed of 300-;
b. fermentation culture: inoculating the seed solution prepared in the step a into a fermentation tank filled with a fermentation culture medium according to the inoculation amount of 20% of the volume ratio, and culturing at the temperature of 27-29 ℃, the rotation speed of 300-;
c. feeding: preparing a feed tank according to the feed culture medium proportion, starting feeding when the total sugar is reduced to 3g/100mL, controlling the content of the total sugar to be maintained at 3 +/-0.5 g/100mL, and simultaneously controlling the pH of the fermentation liquor to be within the range of 6.6-6.8 by using ammonia water;
d. culturing for 8 days to obtain fermentation liquor, and detecting the fermentation titer of the 6-demethyl aureomycin.
3. The use of the feed medium according to claim 2 for increasing the fermentation titer of 6-desmethyltetracycline, wherein: the components and the proportion of the seed culture medium in the step a are as follows: calculated by mass volume ratio, 2.5-4.5 percent of corn starch, 1.5-2.5 percent of soybean cake powder, 0-1.0 percent of yeast extract powder, 1-1.5 percent of ammonium sulfate, 0.2-0.5 percent of light calcium carbonate, 0.1-0.2 percent of sodium bromide, 0.01-0.03 percent of magnesium sulfate and the balance of water.
4. The use of the feed medium according to claim 2 for increasing the fermentation titer of 6-desmethyltetracycline, wherein: in the step b, the formula of the fermentation medium is as follows: by mass volume ratio, 4.0-6.0% of corn starch, 2.0-2.5% of soybean cake powder, 0.5-1.0% of yeast extract powder, 0.2-0.5% of ammonium sulfate, 0.5-1.0% of light calcium carbonate, 0.1-0.2% of sodium bromide, 0.01-0.03% of magnesium sulfate, 0.4% of alpha amylase (W/W of the amount of corn flour), 0.01-0.03% of defoaming agent and the balance of water.
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| CN111560414A (en) * | 2020-05-28 | 2020-08-21 | 河北圣雪大成制药有限责任公司 | Fermentation medium for producing demethylated aureomycin |
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| CN108018328A (en) * | 2016-11-03 | 2018-05-11 | 上海医药工业研究院 | It is a kind of to be used for the culture medium and fermentation process to Ledermycin that ferment |
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| CN110699314A (en) * | 2019-10-22 | 2020-01-17 | 河北圣雪大成制药有限责任公司 | Method for producing 6-demethyltetracycline by fermentation |
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