CN112375798A - Method for producing doramectin by microbial fermentation - Google Patents
Method for producing doramectin by microbial fermentation Download PDFInfo
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Abstract
The invention provides a method for producing doramectin by microbial fermentation, which relates to the technical field of fermentation and comprises the following steps: (1) inoculating the seed liquid cultured by the slant culture medium and the seed culture medium into a fermentation culture medium for fermentation culture; (2) adding fermentation induction additives at the early stage, the middle stage and the later stage of fermentation to obtain doramectin after the fermentation is finished; wherein, the fermentation medium comprises: starch, amylase, cottonseed meal, soybean meal, yeast powder, sodium chloride, light calcium carbonate, pantothenic acid, soybean lecithin, sodium cyclohexanecarboxylate and water. The method can effectively promote the secondary metabolism of the streptomyces avermitilis to produce the doramectin, and the titer of the obtained doramectin is high.
Description
Technical Field
The invention relates to the technical field of fermentation, in particular to a method for producing doramectin by microbial fermentation.
Background
Doramectin is a macrolide antiparasitic drug, and is an abamectin antibiotic prepared by fermenting a new streptomyces avermitilis strain which takes cyclicarboxydic acid as a precursor through gene recombination. The doramectin is a secondary metabolite of the streptomyces avermitilis, generally, a carbon source, a nitrogen source, temperature and the like can influence the fermentation production of the streptomyces avermitilis, the addition of a precursor substance, namely cyclohexanecarboxylic acid or a salt thereof, is very critical in the fermentation process, although the content of the precursor substance cannot influence the activity of the streptomyces avermitilis, the doramectin also becomes a doramectin production short plate when the content of the cyclohexanecarboxylic acid is low, and the doramectin has an inhibition effect on the metabolism of the streptomyces avermitilis when the content of the doramectin is high.
Chinese patent CN109576196A discloses a fermentation medium for producing doramectin and a production method of doramectin, wherein the fermentation medium comprises the following components: 100g/L of starch, 0.1-0.2g/L of amylase, 12-18g/L of soybean cake powder, 12-18g/L of cottonseed cake powder, 0.5-1.5g/L of yeast powder, 0.01-0.2g/L of 2, 2-methylbutyric acid and 0.2-0.4g/L of cyclohexanecarboxylic acid or sodium cyclohexanecarboxylate. The invention obviously improves the fermentation level of doramectin by improving the fermentation culture medium and the doramectin production method, the titer reaches 3545 mu g/ml after the fermentation is carried out for 370 hours, and the whole production process is simple and easy to operate and is beneficial to industrial production. However, the method is mainly researched for a fermentation medium, wherein the cyclohexanecarboxylic acid and other components are directly added and are not supplemented except sugar, so that the fermentation efficiency and the yield of doramectin are possibly influenced.
In view of the above problems, some researchers have recently studied ways of supplementing precursors, carbon sources, and nitrogen sources at different times to promote the production of doramectin. For example, chinese patent CN104651427B discloses a method for producing doramectin, which controls the production of doramectin by controlling the feeding time, frequency, etc. of cyclohexanecarboxylic acid or a salt thereof and a feeding sugar, and the resulting method is suitable for producing doramectin by fermentation in a 500L fermenter. However, the invention is optimized mainly by combining conventional materials with supplementary cases, and although the production of the doramectin can be promoted to a certain extent, the final yield can be expected, the short plate of the cyclic carboxylic acid or the salt thereof in the fermentation process is still difficult to overcome, and the average fermentation unit of the doramectin obtained is low.
Aiming at the problems of low fermentation level, low efficiency and the like of the existing doramectin production method, a production method of doramectin with high efficiency needs to be found urgently, and further, the production of doramectin by the secondary metabolism of streptomyces avermitilis is promoted.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a method for producing doramectin by microbial fermentation. The method can effectively promote the secondary metabolism of the streptomyces avermitilis to produce the doramectin, and the titer of the obtained doramectin is higher.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides a method for producing doramectin by microbial fermentation, which comprises the following steps:
(1) inoculating the seed liquid cultured by the slant culture medium and the seed culture medium into a fermentation culture medium for fermentation culture;
(2) adding fermentation induction additives at the early stage, the middle stage and the later stage of fermentation to obtain doramectin after the fermentation is finished;
the fermentation medium comprises: starch, amylase, cottonseed meal, soybean meal, yeast powder, sodium chloride, light calcium carbonate, pantothenic acid, soybean lecithin, sodium cyclohexanecarboxylate and water.
Further, the fermentation medium comprises: 120g/L of starch 110-.
Preferably, the fermentation medium comprises: 115g/L of starch, 0.1g/L of amylase, 15g/L of cottonseed cake powder, 12g/L of soybean cake powder, 1g/L of yeast powder, 2g/L of sodium chloride, 8g/L of light calcium carbonate, 0.001g/L of pantothenic acid, 3g/L of soybean lecithin, 0.1/L of sodium cyclohexanecarboxylate and the balance of water.
Further, the fermentation-inducing supplement comprises: sodium cyclohexenoate and soy isoflavones.
Further, the fermentation induction supplements supplemented at different fermentation periods are respectively (the unit of supplementation is specifically the relationship of the total amount of supplementation in the total amount of the culture medium):
and (3) fermentation early stage: 0.3-0.5g/L of sodium cyclohexanecarboxylate and 0.5-0.8g/L of soybean isoflavone;
in the middle stage of fermentation: 0.5-0.8g/L of sodium cyclohexanecarboxylate and 0.4-0.5g/L of soybean isoflavone;
and (3) in the later fermentation stage: 0.2-0.3g/L of sodium cyclohexanecarboxylate and 0.2-0.4g/L of soybean isoflavone.
Preferably, the fermentation induction supplements which are added at different fermentation periods are respectively:
and (3) fermentation early stage: 0.4g/L of sodium cyclohexanecarboxylate and 0.6g/L of soybean isoflavone;
in the middle stage of fermentation: 0.6g/L of sodium cyclohexanecarboxylate and 0.5g/L of soybean isoflavone;
and (3) in the later fermentation stage: 0.2g/L of sodium cyclohexanecarboxylate and 0.3g/L of soybean isoflavone.
Further, the fermentation induction additives added in the middle and later stages of fermentation also comprise maltodextrin, and the addition amount of the maltodextrin in the middle stage of fermentation is 10-12g/L, preferably 10 g/L; the addition amount of maltodextrin at the later stage of fermentation is 12-18g/L, preferably 15 g/L.
Further, when the early stage of fermentation is fermentation culture for 25-35h, the middle stage of fermentation is fermentation culture for 90-120h, and the late stage of fermentation is fermentation culture for 185-200 h. Preferably, when the early fermentation stage is fermentation culture for 30 hours, the middle fermentation stage is fermentation culture for 100 hours, and the late fermentation stage is fermentation culture for 190 hours.
Further, the culture conditions of the fermentation medium are as follows: the temperature of the tank is 25-30 ℃, the pressure of the tank is 0.03-0.05Mpa, and the air flow is 50-100m3The rotation speed is 80-120rpm, and the culture period is 256-262 h. Preferably, the culture conditions of the fermentation medium are: the temperature of the tank is 28 ℃, the pressure of the tank is 0.04Mpa, and the air flow is 80m3The rotation speed is 100rpm, and the culture period is 260 h.
Further, the weight ratio of pantothenic acid to soybean lecithin in the step (1) is 0.001-0.002: 3.
Further, the slant culture medium in the step (1) comprises, by weight, 1-3% of dew alcohol, 1-3% of soybean cake powder, 1-3% of agar and the balance of water.
Further, the seed culture medium in the step (1) comprises the following components in percentage by weight: 1-2% of corn starch, 0.3-0.4% of glucose, 1-2% of soybean cake powder, 1-2% of cottonseed cake powder and the balance of water.
Further, the culture conditions of the slant culture medium in the step (1) are specifically as follows: adjusting pH to 7, controlling temperature to 28-30 deg.C, culturing for 6-8 days.
Further, the culture conditions of the seed culture medium in the step (1) are specifically as follows: adjusting pH to 7, culturing at 28-30 deg.C for 40-45 hr at 250 r/min.
Further, the amount of inoculation of the fermentation medium was 10%.
The technical effects obtained by the invention are as follows:
the invention aims at the problem that the supplementation of the cyclohexanecarboxylate is carried out in different fermentation periods, so that the adverse effect of excessive or small addition of the cyclohexanecarboxylate on the production of the spinosad is avoided, and meanwhile, researches find that when the soybean isoflavone and the maltodextrin are supplemented together with the sodium cyclohexanecarboxylate in different fermentation periods, the action relationship between an induction fermentation culture medium and a doramectin precursor is effectively driven, the sugar source is supplemented to a certain extent, and meanwhile, related components in the fermentation culture medium, such as pantothenic acid and soybean lecithin, generate certain related influence on the pantothenic acid and the soybean lecithin, so that the secondary metabolite production is promoted.
Detailed Description
It is worth to be noted that the streptomyces avermitilis used in the present invention is a streptomyces avermitilis mutant conventionally used in the art, specifically, streptomyces avermitilis mutant ATCC 53568, and the rest of the raw materials are all common commercially available products, and thus the source thereof is not particularly limited.
Example 1
A method for producing doramectin by microbial fermentation comprises the following steps:
(1) inoculating a seed solution cultured by a slant culture medium and a seed culture medium into a fermentation culture medium for fermentation culture, wherein the inoculation amount of the fermentation culture medium is 10%;
(2) adding fermentation induction additives at the early stage, the middle stage and the later stage of fermentation to obtain doramectin after the fermentation is finished;
wherein, the fermentation medium comprises: 110g/L of starch, 0.08g/L of amylase, 14g/L of cottonseed meal, 8g/L of soybean meal, 0.5g/L of yeast powder, 1g/L of sodium chloride, 8g/L of light calcium carbonate, 0.001g/L of pantothenic acid, 2g/L of soybean lecithin, 0.1/L of sodium cyclohexanecarboxylate and the balance of water. The culture conditions of the fermentation medium are as follows: the temperature of the tank is 25 ℃, the pressure of the tank is 0.03Mpa, and the air flow is 50m3The rotation speed is 80rpm, and the culture period is 262 h.
The fermentation induction additives supplemented in different fermentation periods are respectively (the unit of supplementation is the relationship of the total supplementation amount in the total amount of the culture medium):
fermentation early stage (fermentation culture time of 25 h): 0.3g/L of sodium cyclohexanecarboxylate and 0.5g/L of soybean isoflavone;
middle fermentation stage (fermentation culture time of 90 h): 0.5g/L of sodium cyclohexanecarboxylate, 0.4g/L of soybean isoflavone and 10g/L of maltodextrin;
late fermentation (185 h fermentation culture): 0.2g/L of sodium cyclohexanecarboxylate, 0.2g/L of soybean isoflavone and 12g/L of maltodextrin.
The slant culture medium in the step (1) comprises, by weight, 1% of dew alcohol, 1% of soybean cake powder, 1% of agar and the balance of water. The culture conditions are specifically as follows: adjusting pH to 7, and culturing at 28 deg.C for 8 days. The seed culture medium comprises the following components in percentage by weight: 1% of corn starch, 0.3% of glucose, 1% of soybean cake powder, 1% of cottonseed cake powder and the balance of water. The culture conditions are specifically as follows: adjusting the pH value to 7, culturing at 28 deg.C for 45h at 250 r/min.
Example 2
A method for producing doramectin by microbial fermentation comprises the following steps:
(1) inoculating a seed solution cultured by a slant culture medium and a seed culture medium into a fermentation culture medium for fermentation culture, wherein the inoculation amount of the fermentation culture medium is 10%;
(2) adding fermentation induction additives at the early stage, the middle stage and the later stage of fermentation to obtain doramectin after the fermentation is finished;
wherein, the fermentation medium comprises: 120g/L of starch, 0.15g/L of amylase and cottonseed cake16g/L of powder, 15g/L of soybean cake powder, 1.5g/L of yeast powder, 3g/L of sodium chloride, 10g/L of light calcium carbonate, 0.002g/L of pantothenic acid, 5g/L of soybean lecithin, 0.2/L of sodium cyclohexanecarboxylate and the balance of water. The culture conditions of the fermentation medium are as follows: the temperature of the tank is 30 ℃, the pressure of the tank is 0.05Mpa, and the air flow is 100m3The rotation speed is 120rpm, and the culture period is 256 hours.
The fermentation induction additives supplemented in different fermentation periods are respectively (the unit of supplementation is the relationship of the total supplementation amount in the total amount of the culture medium):
fermentation early stage (fermentation culture time of 35 h): 0.5g/L of sodium cyclohexanecarboxylate and 0.8g/L of soybean isoflavone;
middle fermentation stage (fermentation culture time 120 h): 0.8g/L of sodium cyclohexanecarboxylate, 0.5g/L of soybean isoflavone and 12g/L of maltodextrin;
and in the later fermentation stage (during fermentation culture for 200 h): 0.3g/L of sodium cyclohexanecarboxylate, 0.4g/L of soybean isoflavone and 18g/L of maltodextrin.
The slant culture medium in the step (1) comprises 3% of dew alcohol, 3% of soybean cake powder, 3% of agar and the balance of water by weight percentage. The culture conditions are specifically as follows: adjusting pH to 7, and culturing at 30 deg.C for 6 days. The seed culture medium comprises the following components in percentage by weight: 2% of corn starch, 0.4% of glucose, 2% of soybean cake powder, 2% of cottonseed cake powder and the balance of water. The culture conditions are specifically as follows: adjusting pH to 7, culturing at 30 deg.C for 40h at 250 r/min.
Example 3
A method for producing doramectin by microbial fermentation comprises the following steps:
(1) inoculating a seed solution cultured by a slant culture medium and a seed culture medium into a fermentation culture medium for fermentation culture, wherein the inoculation amount of the fermentation culture medium is 10%;
(2) adding fermentation induction additives at the early stage, the middle stage and the later stage of fermentation to obtain doramectin after the fermentation is finished;
wherein, the fermentation medium comprises: 115g/L of starch, 0.1g/L of amylase, 15g/L of cottonseed cake powder, 12g/L of soybean cake powder, 1g/L of yeast powder, 2g/L of sodium chloride, 8g/L of light calcium carbonate, 0.001g/L of pantothenic acid, 3g/L of soybean lecithin, 0.1/L of sodium cyclohexanecarboxylate and the balance of water.The culture conditions of the fermentation medium are as follows: the temperature of the tank is 28 ℃, the pressure of the tank is 0.04Mpa, and the air flow is 80m3The rotation speed is 100rpm, and the culture period is 260 h.
The fermentation induction additives supplemented in different fermentation periods are respectively (the unit of supplementation is the relationship of the total supplementation amount in the total amount of the culture medium):
fermentation early stage (fermentation culture time of 30 h): 0.4g/L of sodium cyclohexanecarboxylate and 0.6g/L of soybean isoflavone;
middle fermentation stage (100 h fermentation culture): 0.6g/L of sodium cyclohexanecarboxylate, 0.5g/L of soybean isoflavone and 10g/L of maltodextrin;
and in the later fermentation stage (when the fermentation culture lasts for 190 h): 0.2g/L of sodium cyclohexanecarboxylate, 0.3g/L of soybean isoflavone and 15g/L of maltodextrin.
The slant culture medium in the step (1) comprises 2% of dew alcohol, 2% of soybean cake powder, 2% of agar and the balance of water by weight percentage. The culture conditions are specifically as follows: the pH was adjusted to 7 and the temperature was adjusted to 28 ℃ and the culture was carried out for 7 days. The seed culture medium comprises the following components in percentage by weight: 1.5% of corn starch, 0.3% of glucose, 1.5% of soybean cake powder, 1.5% of cottonseed cake powder and the balance of water. The culture conditions are specifically as follows: adjusting pH to 7, culturing at 28 deg.C for 42h at 250 r/min.
Comparative example 1
The only difference from example 3 is that the fermentation medium comprises: 100g/L of starch, 0.2g/L of amylase, 12g/L of cottonseed meal, 18g/L of soybean meal, 0.3g/L of yeast powder, 5g/L of sodium chloride, 6g/L of light calcium carbonate, 0.003g/L of pantothenic acid, 1g/L of soybean lecithin, 0.6/L of sodium cyclohexanecarboxylate and the balance of water.
Comparative example 2
The only difference from example 3 is that no fermentation inducing supplement was added.
Comparative example 3
The only difference from example 3 is that the fermentation-inducing supplement does not contain soy isoflavones.
Comparative example 4
The only difference from example 3 is that no pantothenic acid and no soya lecithin were added to the fermentation medium.
Comparative example 5
The only difference from example 3 is that the fermentation induction supplements were only fed in the early stages of fermentation, including: 1.2g/L of sodium cyclohexanecarboxylate, 1.4g/L of soybean isoflavone and 25g/L of maltodextrin.
The concentration of the antibiotic in the fermentation broth, called fermentation unit, is also called titer, and can measure the effective components and performance of the antibiotic, generally, the higher the total fermentation unit (product of fermentation unit and fermentation broth volume) is, the smaller the fixed cost for putting people on unit yield is, and the higher the economic benefit is, after the fermentation culture is finished, the fermentation broth is filtered by filter paper, and then the fermentation titer of doramectin in each embodiment and comparative example is measured and calculated, and table 1 is obtained.
TABLE 1
| Examples of the invention | Potency (mg/L) |
| Example 1 | 2107 |
| Example 2 | 2215 |
| Example 3 | 2239 |
| Comparative example 1 | 1903 |
| Comparative example 2 | 1430 |
| Comparative example 3 | 1894 |
| Comparative example 4 | 1975 |
| Comparative example 5 | 1658 |
As can be seen from Table 1, the titer of doramectin in 256-262h in the examples of the invention is 2107-2239mg/L, wherein the optimum value in example 3 is 2239 mg/L. The potency of doramectin in the comparative examples 1-5 is obviously lower than that of the example 3, wherein the influence of the content of the components of the fermentation culture medium on the production of doramectin can be known in the comparative example 1 and the example 3, the effect of the doramectin obtained finally is remarkably reduced because no fermentation induction additive is added in the comparative example 2, and the potency is relatively poor due to the fact that the fermentation induction additive is added in the comparative example 5, although the fermentation induction additive is added in the early stage of fermentation, the addition amount is the same as the addition amount of the whole period, and the critical effect of doramectin supplemented in the invention can be seen; when the fermentation induction supplement does not contain the soybean isoflavone, as shown in comparative example 3, the titer is relatively low, and the soybean isoflavone can effectively induce the driving property between the cyclohexanecarboxylate and the fermentation medium in the technical scheme of the invention. Comparative example 4, on the other hand, can show the effect on potency of key components in the fermentation medium of the present application, such as pantothenic acid and soya lecithin.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A method for producing doramectin by microbial fermentation is characterized in that: the method comprises the following steps:
(1) inoculating the seed liquid cultured by the slant culture medium and the seed culture medium into a fermentation culture medium for fermentation culture;
(2) adding fermentation induction additives at the early stage, the middle stage and the later stage of fermentation to obtain doramectin after the fermentation is finished;
the fermentation medium comprises: starch, amylase, cottonseed meal, soybean meal, yeast powder, sodium chloride, light calcium carbonate, pantothenic acid, soybean lecithin, sodium cyclohexanecarboxylate and water.
2. The method of claim 1, wherein: the fermentation medium comprises: 120g/L of starch 110-.
3. The method of claim 1, wherein: the fermentation induction additive comprises: sodium cyclohexenoate and soy isoflavones.
4. The method of claim 3, wherein: the fermentation induction additives supplemented in different fermentation periods are respectively as follows:
and (3) fermentation early stage: 0.3-0.5g/L of sodium cyclohexanecarboxylate and 0.5-0.8g/L of soybean isoflavone;
in the middle stage of fermentation: 0.5-0.8g/L of sodium cyclohexanecarboxylate and 0.4-0.5g/L of soybean isoflavone;
and (3) in the later fermentation stage: 0.2-0.3g/L of sodium cyclohexanecarboxylate and 0.2-0.4g/L of soybean isoflavone.
5. The method of claim 4, wherein: the fermentation induction supplementary agent added in the middle and later fermentation stages also comprises maltodextrin, the supplementary amount of the maltodextrin in the middle fermentation stage is 10-12g/L, and the supplementary amount of the maltodextrin in the later fermentation stage is 12-18 g/L.
6. The method of claim 1, wherein: the early fermentation period is 25-35h, the middle fermentation period is 90-120h, and the later fermentation period is 185-200 h.
7. The method of claim 1, wherein: the culture conditions of the fermentation culture medium are as follows: the temperature of the tank is 25-30 ℃, the pressure of the tank is 0.03-0.05Mpa, and the air flow is 50-100m3The rotation speed is 80-120rpm, and the culture period is 256-262 h.
8. The method of claim 1, wherein: the weight ratio of the pantothenic acid to the soybean lecithin in the step (1) is 0.001-0.002: 3.
9. The method of claim 1, wherein: the slant culture medium in the step (1) comprises, by weight, 1-3% of dew alcohol, 1-3% of soybean cake powder, 1-3% of agar and the balance of water.
10. The method of claim 1, wherein: the seed culture medium in the step (1) comprises the following components in percentage by weight: 1-2% of corn starch, 0.3-0.4% of glucose, 1-2% of soybean cake powder, 1-2% of cottonseed cake powder and the balance of water.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104561180A (en) * | 2014-12-26 | 2015-04-29 | 宁夏泰瑞制药股份有限公司 | Culture mediums for producing doramectin through fermentation of mutant streptomyces avermitilis and material supplement method |
| CN104651427A (en) * | 2015-01-21 | 2015-05-27 | 丽珠集团新北江制药股份有限公司 | Method for preparing doramectin |
| CN108018324A (en) * | 2016-10-28 | 2018-05-11 | 北大方正集团有限公司 | A kind of fermentation medium for producing doractin and preparation method and application |
| CN108396045A (en) * | 2018-02-24 | 2018-08-14 | 湖北宏中药业股份有限公司 | A kind of high yield fermentation method for producing of doractin |
| CN109576196A (en) * | 2019-01-25 | 2019-04-05 | 北大方正集团有限公司 | A kind of production method of the fermentation medium for producing doractin and doractin |
-
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- 2020-11-05 CN CN202011222671.4A patent/CN112375798B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104561180A (en) * | 2014-12-26 | 2015-04-29 | 宁夏泰瑞制药股份有限公司 | Culture mediums for producing doramectin through fermentation of mutant streptomyces avermitilis and material supplement method |
| CN104651427A (en) * | 2015-01-21 | 2015-05-27 | 丽珠集团新北江制药股份有限公司 | Method for preparing doramectin |
| CN108018324A (en) * | 2016-10-28 | 2018-05-11 | 北大方正集团有限公司 | A kind of fermentation medium for producing doractin and preparation method and application |
| CN108396045A (en) * | 2018-02-24 | 2018-08-14 | 湖北宏中药业股份有限公司 | A kind of high yield fermentation method for producing of doractin |
| CN109576196A (en) * | 2019-01-25 | 2019-04-05 | 北大方正集团有限公司 | A kind of production method of the fermentation medium for producing doractin and doractin |
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