CN107723325B - Fermentation production method of doramectin based on pH control - Google Patents
Fermentation production method of doramectin based on pH control Download PDFInfo
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Abstract
The invention relates to the technical field of microbial medicines, in particular to a doramectin fermentation production method based on pH control. The method comprises the following steps: in the primary metabolism stage of doramectin producing bacteria, hypha can grow rapidly through a basic culture medium, and the pH is not controlled; in the secondary metabolism stage, the pH is controlled within the range of 6.7-7.0 by supplementing physiological alkaline salt and feeding the first carbon source. The method according to the present invention can promote a rapid increase in doramectin synthesis and maintain a rapid synthesis rate for a long time. The method has simple and easy process and easy operation, and is very suitable for commercial production.
Description
Technical Field
The invention relates to the technical field of microbial medicines, in particular to a doramectin fermentation production method based on pH control.
Background
Doramectin (doramectin) is a new generation macrolide antiparasitic drug, is a cyclohexane carboxylic acid (CHC) precursor isomer (namely 25-cyclohexane avermectin B1) of avermectin B1, and can be biosynthesized by adding cyclohexane carboxylic acid as a precursor in the fermentation process of Streptomyces avermitilis mutants. Because doramectin has the advantages of wide antiparasitic range (3 class, 12 order and 73 genus parasites are sensitive to doramectin in clinic), obvious effect, easy control of administration route, high bioavailability, long drug residual effect period and the like, doramectin is clinically applied to mammals such as cows, horses, sheep, goats, pigs, camels, dogs and the like in veterinarians. The structural formula of doramectin is as follows:
the fermentation process of microorganisms is generally divided into two stages, primary metabolism and secondary metabolism. In the primary metabolic stage, which is mainly responsible for the growth of the mycelium, it is necessary to provide basic raw materials such as glucose and phosphate, which are required for rapid growth, and, of course, an easily available nitrogen source. The doramectin producing strain streptomyces avermitilis can grow rapidly at the pH value of 7.0. Along with the rapid growth of the thalli, the pH value of the fermentation liquor is gradually reduced by a large amount of organic acid generated by primary metabolism, and the fermentation process enters a secondary metabolism stage. The biosynthesis of doramectin requires a proper pH range, and the synthesis of target products is not facilitated by too high or too low a pH value.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a doramectin fermentation production method based on pH control, and a doramectin fermentation process with high synthesis rate and high fermentation yield is obtained by controlling different pH ranges at different stages of the doramectin producing strain fermentation process.
The specific technical scheme of the invention is as follows:
the invention provides a doramectin fermentation production method based on pH control, which comprises the following steps of:
in the primary metabolism stage of doramectin producing bacteria, hypha can grow rapidly through a basic culture medium, and the pH is not controlled; in the secondary metabolism stage, the pH is controlled within the range of 6.7-7.0 by supplementing physiological alkaline salt and feeding the first carbon source.
According to one embodiment of the invention, the basal medium contains phosphate and a second carbon source.
According to one embodiment of the present invention, the physiological basic salt is selected from one or more of trimagnesium phosphate, trimagnesium phosphate hydrate (e.g., trimagnesium phosphate tetrahydrate, trimagnesium phosphate pentahydrate, etc.), potassium acetate, sodium acetate, and the like.
According to one embodiment of the present invention, the first carbon source is selected from one or more of starch, glucose, dextrin, maltose and maltodextrin.
According to one embodiment of the invention, the physiological alkaline salt is added in an amount of not more than 3 g/L and the first carbon source is added in an amount of 30-60 g/L per liter of the fermentation broth during the secondary metabolism stage.
According to one embodiment of the present invention, the phosphate is selected from one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, trimagnesium phosphate, and trimagnesium phosphate hydrate.
According to one embodiment of the present invention, the second carbon source is selected from one or more of starch, glucose, maltose, dextrin, and maltodextrin.
According to one embodiment of the invention, the phosphate is added in an amount of 2-9 g/L and the second carbon source is added in an amount of 90-110 g/L per liter of the basal medium.
According to one embodiment of the invention, each liter of the basic culture medium further comprises 5-20 g of soybean cake powder, 5-20 g of cottonseed cake powder, 1-5 g of calcium carbonate, 0.5-1.5 g of sodium chloride, 0.6-1.0 g of antifoaming agent, and the balance of water.
According to one embodiment of the invention, the culture conditions in the primary and secondary metabolic stages are both: the culture temperature is 27.5-29.5 ℃, the stirring speed is 80-220rpm, and the air flow is 1:0.5-0.8 vvm.
The invention adopts a two-stage pH control strategy, in the primary metabolism stage of doramectin bacteria, the hyphae can grow rapidly by adding glucose and phosphate in a basic culture medium, and the pH is not controlled; the pH value is gradually decreased from low to high within 0-90 hours and is not more than 7.2 at the maximum, and then gradually decreased to 6.3-6.5 within about 120 hours. And then physiological alkaline salt is supplemented in the secondary metabolism stage, the pH is controlled to be in the range of 6.7-7.0 optimally by matching with fed-batch carbon source, the optimal pH value required by doramectin biosynthesis is met, the rapid increase of doramectin synthesis is promoted, the long-time rapid synthesis rate is maintained, and the doramectin fermentation yield in 250-300 hours reaches 2100-2300 ug/ml. The method has simple and easy process and easy operation, and is very suitable for commercial production.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. The invention covers all possible alternatives, modifications and equivalents within the scope of the claims. The specific techniques or conditions not mentioned in the following examples are all the conventional techniques or conditions, or the techniques or conditions described in the literature in the field, or the product specification.
In the invention, the content of doramectin is determined by an HPLC high performance liquid detection method, which is specifically as follows.
Column determination: c18 column, 4.6mm X250 mm X5 um, column temperature: 30 ℃; isocratic elution is adopted, and the mobile phase is methanol, water and acetonitrile (8:1: 1); the flow rate is 1.0 mL/min; detection wavelength: 245 nm; sample introduction amount: 10 μ L. And calculating the content of doramectin according to an area normalization method.
Example 1
Strain: streptomyces avermitilis ATCC 53568
The fermentation medium proportion is as follows:
accurately weighing starch according to a specified ratio, putting the starch into a fermentation proportioning tank (adding a proper amount of water in advance), starting stirring, adding amylase (0.5 percent of the weight of the starch) steam, heating, gradually raising the temperature to 85 ℃, preserving heat and stirring for 60 minutes to fully liquefy the starch. And putting the ingredients into a dosing tank, adding water to a constant volume, stirring for 15 minutes, measuring the pH value until the pH value is 6.9, heating, and sterilizing for 30 minutes when the temperature reaches 121 ℃.
Fermentation volume: 600L
Inoculation amount: 10 percent of
The culture temperature is as follows: 27.5-29.5 deg.C
Stirring speed: 80-220rpm
Air flow rate: 1:0.5-0.8vvm
And (3) culture period: 270-300 hours
In the early fermentation stage of doramectin producing bacteria, hyphae can grow rapidly through a basic culture medium, and the pH is not controlled.
Fermentation precursor supplement: cyclohexanecarboxylic acid was formulated as the sodium salt, and the total amount was 0.18% by weight of sodium cyclohexanecarboxylate. Culturing in fermenter for 40hr, adding 0.08wt% cyclohexanecarboxylic acid; when the fermentation tank is cultured for 110-130hr, 0.05wt% of cyclohexanecarboxylic acid is added; adding 0.05wt% of cyclohexanecarboxylic acid when culturing in the fermenter for 210-220 hrs.
And (3) fermentation and sugar supplement: during the secondary metabolism stage (fermentation period 130-280 hours), a maltodextrin solution (300 g/L of maltodextrin) and a trimagnesium phosphate suspension (30.0 g/L of trimagnesium phosphate suspension) were added, the total sugar content was controlled to be about 2.0-4.0%, and the pH was controlled to be in the range of 6.7-6.9. And (3) respectively supplementing for multiple times, wherein the total supplementing amount is as follows: the amount of maltodextrin was 30.0 g and the amount of trimagnesium phosphate was 1.5 g per liter of the fermentation broth. During the fermentation, the pH value is controlled to be 6.7-6.9, and the pH value at 288 th hour of fermentation is 7.0.
Taking 2 ml of fermentation liquid, adding 10 ml of ethanol, shaking for 15 minutes, centrifuging at high speed to obtain supernatant, analyzing the content of doramectin by HPLC, and obtaining the titer of the doramectin at 288 hours of fermentation to be 2.11 g/L.
Example 2
Strain: streptomyces avermitilis ATCC 53568
The fermentation medium proportion is as follows:
accurately weighing starch according to a specified ratio, putting the starch into a fermentation proportioning tank (adding a proper amount of water in advance), starting stirring, adding amylase (0.5 percent of the weight of the starch) steam, heating, gradually raising the temperature to 85 ℃, preserving heat and stirring for 60 minutes to fully liquefy the starch. And putting the ingredients into a dosing tank, adding water to a constant volume, stirring for 15 minutes, measuring the pH value until the pH value is 6.9, heating, and sterilizing for 30 minutes when the temperature reaches 121 ℃.
Fermentation volume: 600L
Inoculation amount: 10 percent of
The culture temperature is as follows: 27.5-29.5 deg.C
Stirring speed: 80-220rpm
Air flow rate: 1:0.5-0.8vvm
Culture period of 270-300 hours
In the early fermentation stage of doramectin producing bacteria, hyphae can grow rapidly through a basic culture medium, and the pH is not controlled.
Fermentation precursor supplement: cyclohexanecarboxylic acid was formulated as the sodium salt, and the total amount was 0.18% by weight of sodium cyclohexanecarboxylate. Culturing in fermenter for 40hr, adding 0.08wt% cyclohexanecarboxylic acid; when the fermentation tank is cultured for 110-130hr, 0.05wt% of cyclohexanecarboxylic acid is added; adding 0.05wt% of cyclohexanecarboxylic acid when culturing in the fermenter for 210-220 hrs.
And (3) fermentation and sugar supplement: during the secondary metabolism stage (fermentation period 130-280 hours), dextrin solution (dextrin concentration is 300 g/L), magnesium phosphate tribasic suspension (magnesium phosphate tribasic suspension pentahydrate concentration is 30.0 g/L) and potassium acetate solution (potassium acetate solution, potassium acetate concentration is 10 g/L) are added, the total sugar content is controlled to be about 2.0-5.0%, and the pH is controlled to be in the range of 6.7-6.9. And (3) respectively supplementing for multiple times, wherein the total supplementing amount is as follows: relative to each liter of fermentation liquor, 40.0 g of dextrin, 1.6 g of magnesium phosphate trihydrate and 0.6 g of potassium acetate. During the fermentation, the pH value is controlled at 6.7-7.0, and the pH value at 300 hours of fermentation is 7.1.
Taking 2 ml of fermentation liquid, adding 10 ml of ethanol, shaking for 15 minutes, centrifuging at high speed to obtain supernatant, analyzing the content of doramectin by HPLC, and obtaining the titer of the doramectin at 300 hours of fermentation to be 2.18 g/L.
Example 3
Strain: streptomyces avermitilis ATCC 53568
The fermentation medium proportion is as follows:
accurately weighing starch according to a specified ratio, putting the starch into a fermentation proportioning tank (adding a proper amount of water in advance), starting stirring, adding amylase (0.5 percent of the weight of the starch) steam, heating, gradually raising the temperature to 85 ℃, preserving heat and stirring for 60 minutes to fully liquefy the starch. And putting the ingredients into a dosing tank, adding water to a constant volume, stirring for 15 minutes, measuring the pH value until the pH value is 6.9, heating, and sterilizing for 30 minutes when the temperature reaches 121 ℃.
Fermentation volume: 6000L
Inoculation amount: 10 percent of
The culture temperature is as follows: 27.5-29.5 deg.C
Stirring speed: 80-220rpm
Air flow rate: 1:0.5-0.8vvm
And (3) culture period: 270-300 hours
In the early fermentation stage of doramectin producing bacteria, hyphae can grow rapidly through a basic culture medium, and the pH is not controlled.
Fermentation precursor supplement: cyclohexanecarboxylic acid was formulated as the sodium salt, and the total amount was 0.18% by weight of sodium cyclohexanecarboxylate. Culturing in fermenter for 40hr, adding 0.08wt% cyclohexanecarboxylic acid; when the fermentation tank is cultured for 110-130hr, 0.05wt% of cyclohexanecarboxylic acid is added; adding 0.05wt% of cyclohexanecarboxylic acid when culturing in the fermenter for 210-220 hrs.
And (3) fermentation and sugar supplement: during the secondary metabolism stage (fermentation period 130-280 hours), a maltodextrin solution (300 g/L of maltodextrin), a magnesium phosphate tribasic suspension (30.0 g/L of magnesium phosphate tribasic suspension) and a sodium acetate solution (10 g/L of sodium acetate solution) were added, the total sugar content was controlled to be about 2.0-4.0%, and the pH was controlled to be in the range of 6.7-6.9. And (3) respectively supplementing for multiple times, wherein the total supplementing amount is as follows: relative to each liter of fermentation liquor, 60.0 grams of maltodextrin, 2.3 grams of magnesium phosphate tribasic and 0.5 gram of sodium acetate. During the fermentation, the pH value is controlled at 6.7-7.0, and the pH value at 288 th hour of fermentation is 7.0.
Taking 2 ml of fermentation liquid, adding 10 ml of ethanol, shaking for 15 minutes, centrifuging at high speed to obtain supernatant, analyzing the content of doramectin by HPLC, and obtaining the titer of the doramectin at 298 hours of fermentation to be 2.25 g/L.
Example 4
Strain: streptomyces avermitilis ATCC 53568
The fermentation medium proportion is as follows:
accurately weighing starch according to a specified ratio, putting the starch into a fermentation proportioning tank (adding a proper amount of water in advance), starting stirring, adding amylase (0.5 percent of the weight of the starch) steam, heating, gradually raising the temperature to 85 ℃, preserving heat and stirring for 60 minutes to fully liquefy the starch. And putting the ingredients into a dosing tank, adding water to a constant volume, stirring for 15 minutes, measuring the pH value until the pH value is 6.9, heating, and sterilizing for 30 minutes when the temperature reaches 121 ℃.
Fermentation volume: 600L
Inoculation amount: 10 percent of
The culture temperature is as follows: 27.5-29.5 deg.C
Stirring speed: 80-220rpm
Air flow rate: 1:0.5-0.8vvm
And (3) culture period: 270-300 hours
In the early fermentation stage of doramectin producing bacteria, hyphae can grow rapidly through a basic culture medium, and the pH is not controlled.
Fermentation precursor supplement: cyclohexanecarboxylic acid was formulated as the sodium salt, and the total amount was 0.18% by weight of sodium cyclohexanecarboxylate. Culturing in fermenter for 40hr, adding 0.08wt% cyclohexanecarboxylic acid; when the fermentation tank is cultured for 110-130hr, 0.05wt% of cyclohexanecarboxylic acid is added; adding 0.05wt% of cyclohexanecarboxylic acid when culturing in the fermenter for 210-220 hrs.
And (3) fermentation and sugar supplement: during the secondary metabolism stage (fermentation period 130-280 hours), a maltodextrin solution (the concentration of maltodextrin in the maltodextrin solution is 300 g/L) and a trimagnesium phosphate suspension (the concentration of trimagnesium phosphate in the trimagnesium phosphate suspension is 30.0 g/L) are supplemented, the total sugar content is controlled to be about 2.0-4.0%, and the total amount is supplemented: the amount of maltodextrin was 45.0 g and the amount of trimagnesium phosphate was 2.5 g per liter of the fermentation broth. During the fermentation, the pH value is controlled to be 6.7-6.9, and the pH value at 288 th hour of fermentation is 7.0.
Taking 2 ml of fermentation liquid, adding 10 ml of ethanol, shaking for 15 minutes, centrifuging at high speed to obtain supernatant, analyzing the content of doramectin by HPLC, and obtaining the titer of the doramectin at 288 hours of fermentation to be 2.13 g/L.
Comparative example 1
The difference from the example 4 is that only the carbon source maltodextrin is supplemented during the sugar supplement in the fermentation, and the physiological alkaline salt trimagnesium phosphate is not supplemented. During the fermentation, the pH value reaches 6.2 at the lowest, gradually rises back to 6.7 at 280 hours of the fermentation, and the pH value at 300 hours of the fermentation is 7.2.
Taking 2 ml of fermentation liquid, adding 10 ml of ethanol, shaking for 15 minutes, centrifuging at high speed to obtain supernatant, analyzing the content of doramectin by HPLC, and obtaining the titer of the doramectin at 300 hours of fermentation to be 1.45 g/L.
According to the embodiments 1 to 4 of the present invention, in the fermentation stage, physiological alkaline salts such as magnesium phosphate, potassium acetate, and the like are added, and carbon sources such as maltodextrin, dextrin, and the like are added in a flow manner, so that the pH is controlled to be in the range of 6.7 to 7.0 optimally, the rapid increase of the doramectin synthesis is promoted, the long-term rapid synthesis rate is maintained, and the doramectin titer can reach 2.2 g/L. In comparative example 1, only carbon source was added in the fermentation stage, physiological alkaline salt was not added, and in the middle and later stages of fermentation, pH was unstable, which was manifested by a lower pH in the middle stage, a slower increase in titer, a faster rise in pH in the later stage, and a lag in increase in titer, which was lower by more than 30% than the fermentation unit in the three examples in which pH control was performed.
Therefore, the method can control the pH value of the doramectin fermentation engineering within the range of 6.7-7.0, meet the optimal pH value required by doramectin biosynthesis, promote the doramectin synthesis and maintain the rapid synthesis rate for a long time.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (8)
1. A fermentation production method of doramectin based on pH control is characterized by comprising the following steps: the adopted strain is Streptomyces avermitilis ATCC 53568; in the primary metabolism stage of doramectin producing bacteria, hypha can grow rapidly through a basic culture medium, and the pH is not controlled; fermentation precursor supplement: preparing sodium salt from cyclohexanecarboxylic acid, adding 0.18wt% sodium salt of cyclohexanecarboxylic acid, and culturing in fermenter for 40hr, adding 0.08wt% cyclohexanecarboxylic acid; when the fermentation tank is cultured for 110-130hr, 0.05wt% of cyclohexanecarboxylic acid is added; adding 0.05wt% cyclohexanecarboxylic acid when culturing for 210-220 hrs in the fermentation tank; in the secondary metabolism stage, physiological alkaline salt is supplemented, and a first carbon source is fed-batch to control the pH within the range of 6.7-7.0; the physiological alkaline salt is selected from more than one of magnesium phosphate, magnesium phosphate hydrate, potassium acetate and sodium acetate; the first carbon source is selected from more than one of dextrin and maltodextrin.
2. The fermentative doramectin production method according to claim 1, wherein the basal medium contains phosphate and a second carbon source.
3. The fermentative doramectin production method according to claim 1, wherein the physiological alkaline salt is added in an amount of not more than 3 g/L and the first carbon source is added in an amount of 30 to 60 g/L per liter of the fermentation broth in the secondary metabolism stage.
4. The fermentative doramectin production method according to claim 2, wherein the phosphate is one or more selected from the group consisting of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, trimagnesium phosphate, and trimagnesium phosphate hydrate.
5. The method for the fermentative production of doramectin according to claim 2, wherein the second carbon source is one or more selected from the group consisting of starch, glucose, maltose, dextrin and maltodextrin.
6. The fermentative doramectin production method according to claim 2, wherein the phosphate is contained in an amount of 2 to 9 g and the second carbon source is contained in an amount of 90 to 110 g per liter of the basal medium.
7. The method for producing doramectin through fermentation of claim 1, wherein each liter of the basic culture medium further comprises 5-20 g of soybean cake powder, 5-20 g of cottonseed cake powder, 1-5 g of calcium carbonate, 0.5-1.5 g of sodium chloride, 0.6-1.0 g of an antifoaming agent, and the balance of water.
8. The fermentative doramectin production method according to claim 1, wherein the culture conditions in the primary metabolic stage and the secondary metabolic stage are both: the culture temperature is 27.5-29.5 ℃, the stirring speed is 80-220rpm, and the air flow is 1:0.5-0.8 vvm.
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