CN1557957A - Preparation method for improving output of gentamycin - Google Patents
Preparation method for improving output of gentamycin Download PDFInfo
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- CN1557957A CN1557957A CNA2004100391374A CN200410039137A CN1557957A CN 1557957 A CN1557957 A CN 1557957A CN A2004100391374 A CNA2004100391374 A CN A2004100391374A CN 200410039137 A CN200410039137 A CN 200410039137A CN 1557957 A CN1557957 A CN 1557957A
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Abstract
The method of raising gentamicin yield is that into the conventional deep red micromonad fermenting culture medium comprising corn powder, starch, yeast powder or soybean powder, potassium nitrate, calcium carbonate, ammonium sulfate, peptone and cobalt chloride, one or several kinds of additives are added selected from: rice powder, millet powder, fructose, glycosamine, ferric gluconate, zinc chloride, ferrous citrate, ferrous lactate, vitamin B12, etc. The method of the present invention has the advantages of raising gentamicin yield by 5-12 %, lowered cost, and raised fermentation efficiency. The product of the present invention is one kind of antibiotic for human and animal.
Description
Technical field
The present invention relates to antibiotic preparation method, specifically relate to microbial fermentation and improve the preparation method of gentamicin output.
Background technology
Gentamicin is the microbiotic of being produced by deep red micromonospora (Micromonosporapurpurea).It is a multi-component aminoglycosides microbiotic.Its main component is respectively C1, C1a, C2 and C2a.Gentamicin is widely used in treating human diseases and livestock industry.Gentamicin is the active drug that control streptococcus aureus, Pseudomonas aeruginosa, intestinal bacteria and Bacillus proteus etc. infect.
China begins to produce gentamicin in the sixties in last century, and this medicine has become a kind of old medicine in the medicine industry.For a long time, because the limitation of technology self-growth, production yield and production cycle are like reaching capacity.The production fermentation period of this medicine refined yield 85% at 70-130 hour at present, and fermentation efficiency is the 1300-1500 units per ml, therefore, how to improve gentamicin output and becomes the task of top priority.
Summary of the invention
The objective of the invention is to overcome the problem that prior art exists, and a kind of preparation method who improves the gentamicin fermentation efficiency is provided.
The present invention seeks to and can realize by following measure:
The bacterial classification that uses among the present invention is deep red micromonospora (Micromonosporapurpurea bacterial strain NRRL2953) ATCC15835, this bacterium is deposited in (American Type CultureCollection in the U.S. typical case culture collection, P.O.Box 1549, Manassas, VA 20110).
The present invention improves the preparation method of gentamicin output, in conventional fermention medium, add being selected from following one or more additives: hydrolyzed casein, rice powder, millet powder, fructose, glucosamine, ferrous gluconate, zinc chloride, ferrous citrate, iron lactate, Zinc Gluconate, ferric ammonium citrate, riboflavin, thiamine propyl disulfide, vitamin B12, phytic acid, folic acid.Use conventional fermentation process, culture temperature 35-37 ℃, pH6.8-7.6, fermentation time 88-92 hour.
1. substratum is formed
Semen Maydis powder 5-15 grams per liter, starch 10-50 grams per liter, yeast powder or analysis for soybean powder 25-40 grams per liter, saltpetre 0.01-0.45 grams per liter, lime carbonate 2.5-7.5 grams per liter, ammonium sulfate 0.1-3.5 grams per liter, peptone 3.5-7.5 grams per liter, cobalt chloride 5-50 mg/litre.
2. additive: add and be selected from one or more following additives
1) hydrolyzed casein 0.5-50 grams per liter
2) rice powder 0.5-50 grams per liter
3) millet powder 0.5-50 grams per liter
4) fructose 0.5-25 grams per liter
5) glucosamine 0.5-25 grams per liter
6) ferrous gluconate 0.02-0.25 grams per liter
7) zinc chloride 0.01-0.9 grams per liter
8) ferrous citrate 0.01-0.9 grams per liter
9) iron lactate 0.01-0.9 grams per liter
10) Zinc Gluconate 0.01-0.9 grams per liter
11) ferric ammonium citrate 0.005-0.5 grams per liter
12) riboflavin 0.02-0.45 mg/litre
13) thiamine propyl disulfide 0.02-0.45 mg/litre
14) vitamin B12 0.02-0.45 mg/litre
15) phytic acid 0.01-0.5 mg/litre
16) folic acid 0.01-0.2 mg/litre
The gentamicin estimation of biological potency
The standard bacterial classification of measuring the biological value of gentamicin is a bacillus pumilus.With known standardized solution of tiring and tested product solution, drip on the substratum of bacillus pumilus growth and carry out contrast culture, produce transparent inhibition zone.Relatively the size of mark product and tested product inhibition zone is obtained gentamicin antibacterial potency (table 1).
Table 1: the kind of additive is to the influence of gentamicin fermentation efficiency
| Additive | Concentration | Fermentation efficiency (units per ml) |
| Contrast | ??--- | ????1420 |
| Zinc chloride | 0.3 grams per liter | ????2190 |
| Iron lactate | 0.6 grams per liter | ????1990 |
| Ferrous citrate | 0.6 grams per liter | ????1820 |
| Ferric ammonium citrate | 0.3 grams per liter | ????1790 |
| Hydrolyzed casein | 5 grams per liters | ????1760 |
| Ferrous gluconate | 0.06 grams per liter | ????1700 |
| Zinc Gluconate | 0.3 grams per liter | ????1620 |
| Vitamin B12 | 0.05 mg/litre | ????1610 |
| Fructose | 1.8 grams per liter | ????1580 |
| Glucosamine | 1.5 grams per liter | ????1550 |
| Folic acid | 0.05 mg/litre | ????1520 |
| The rice powder | 5 grams per liters | ????1500 |
| Millet powder | 5 grams per liters | ????1480 |
| Riboflavin | 0.05 mg/litre | ????1490 |
| Phytic acid | 0.05 mg/litre | ????1480 |
| Thiamine propyl disulfide | 0.05 mg/litre | ????1470 |
As can be seen from Table 1: the fermentation efficiency of gentamicin adds the variation after the different additive on the basis of substratum.
Make the additive of increase of production amplitude about 5% that riboflavin be arranged, thiamine propyl disulfide, phytic acid, folic acid, millet powder and rice powder; Increasing has glucosamine, fructose, vitamin B12, ferrous gluconate and a Zinc Gluconate about 10-20%; Made the gentamicin increase of production zinc chloride, hydrolyzed casein, ferric ammonium citrate, ferrous citrate and iron lactate (Fig. 1) arranged more than 20%.Add the multiple purpose that also can reach volume increase simultaneously.
The present invention compares the traditional zymotic method and has following advantage: improve more than the gentamicin output 5-20%, reduce cost, increase fermentation efficiency.
Description of drawings:
Fig. 1: gentamicin volume increase per-cent relatively
X-axis is the kind of additive among the figure.
Y-axis is per-cent (%), to contrast 100 as reference.
Among Fig. 1: 1. contrast, 2. fructose, 3. glucosamine, 4. riboflavin, 5. thiamine propyl disulfide, 6. vitamin B12,7. zinc chloride, 8. Zinc Gluconate, 9. ferrous gluconate, 10. ferric ammonium citrate, 11. ferrous citrates, 12. iron lactates, 13. hydrolyzed casein, 14. millet powder, 15. rice powder, 16. folic acid, 17. phytic acid.
Specific implementation method:
Enumerate embodiment below, the present invention is further specified.But the present invention is not only limited to these embodiment.
Embodiment 1: containing Semen Maydis powder 11 grams per liters, starch 35 grams per liters, analysis for soybean powder 32 grams per liters, saltpetre 0.01 grams per liter, lime carbonate 5 grams per liters, ammonium sulfate 0.25 grams per liter, peptone 4.5 grams per liters, in the conventional fermention medium of the deep red micromonospora of cobalt chloride 15 mg/litre, add hydrolyzed casein, concentration 5 grams per liters, inoculate Micromonospora purpurea strain NRRL2953 according to a conventional method, at pH7.2,35 ℃ of culture temperature, the condition bottom fermentation that volume is 8 liters 90 hours.
Embodiment 2: additive is the rice powder, and concentration 0.5 grams per liter replaces hydrolyzed casein concentration 5 grams per liters among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 3: additive is a millet powder, and concentration 0.5 grams per liter replaces hydrolyzed casein concentration 5 grams per liters among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 4: additive is a fructose, and concentration 0.5 grams per liter replaces hydrolyzed casein concentration 5 grams per liters among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 5: additive is a glucosamine, and concentration 0.5 grams per liter replaces hydrolyzed casein concentration 5 grams per liters among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 6: additive is a ferrous gluconate, and concentration 0.02 grams per liter replaces hydrolyzed casein concentration 0.5 grams per liter among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 7: additive is a zinc chloride, and concentration 0.01 mg/litre replaces hydrolyzed casein concentration 0.5 grams per liter among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 8: additive is a ferrous citrate, and concentration 0.01 grams per liter replaces hydrolyzed casein concentration 0.5 grams per liter among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 9: additive is an iron lactate, and concentration 0.01 grams per liter replaces hydrolyzed casein concentration 0.5 grams per liter among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 10: additive is a Zinc Gluconate, and concentration 0.01 grams per liter replaces hydrolyzed casein concentration 0.5 grams per liter among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 11: additive is a ferric ammonium citrate, and concentration 0.005 grams per liter replaces hydrolyzed casein concentration 0.5 grams per liter among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 12: additive is a riboflavin, and concentration 0.02 mg/litre replaces hydrolyzed casein concentration 5 grams per liters among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 13: additive is a thiamine propyl disulfide, and concentration 0.02 mg/litre replaces hydrolyzed casein concentration 0.5 grams per liter among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 14: additive is a vitamin B12, and concentration 0.02 mg/litre replaces hydrolyzed casein concentration 0.5 grams per liter among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 15: additive is a phytic acid, and concentration 0.01 mg/litre replaces hydrolyzed casein concentration 0.5 grams per liter among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 16: additive is a folic acid, and concentration 0.01 mg/litre replaces hydrolyzed casein concentration 0.5 grams per liter among the embodiment 1, and substratum is formed and consumption, and fermentation condition is all identical with embodiment 1.
Embodiment 17: additive is a millet powder, concentration 0.5 grams per liter; Fructose, concentration 0.5 grams per liter; Glucosamine, concentration 0.5 grams per liter; Replace hydrolyzed casein concentration 0.5 grams per liter among the embodiment 1, substratum is formed and consumption, and fermentation condition is all identical with embodiment 1, and output improves 20%.
Embodiment 18: add millet powder on the basis of embodiment 1, concentration 0.5 grams per liter; Fructose, concentration 0.5 grams per liter; Glucosamine, concentration 0.5 grams per liter; Iron lactate, concentration 0.05 grams per liter; Ferric ammonium citrate, concentration 0.05 grams per liter; Zinc Gluconate, concentration 0.01 grams per liter; Riboflavin, concentration 0.02 mg/litre; Thiamine propyl disulfide, concentration 0.02 mg/litre; Vitamin B12, concentration 0.02 mg/litre; Phytic acid, concentration 0.01 mg/litre; Folic acid, concentration 0.01 mg/litre; Substratum is formed and consumption, and fermentation condition is all identical with embodiment 1, and output improves 30%, but the corresponding raising of cost.
Comparative example 1: containing Semen Maydis powder 11 grams per liters, starch 35 grams per liters, analysis for soybean powder 32 grams per liters, saltpetre 0.01 grams per liter, lime carbonate 5 grams per liters, ammonium sulfate 0.25 grams per liter, peptone 4.5 grams per liters, in the conventional fermention medium of the deep red micromonospora of cobalt chloride 15 mg/litre, inoculate Micromonospora purpurea strain NRRL2953 according to a conventional method, at pH7.2,35 ℃ of culture temperature, 8 liters of volumes, condition bottom fermentation 90 hours.
Product of the present invention is used for the treatment of human diseases and livestock industry, makes microbiotic and uses.
Claims (2)
1, improves the preparation method of gentamicin output, it is characterized in that in the conventional fermention medium of deep red micromonospora adding is selected from following one or more additives: hydrolyzed casein, rice powder, millet powder, fructose, glucosamine, ferrous gluconate, zinc chloride, ferrous citrate, iron lactate, Zinc Gluconate, ferric ammonium citrate, riboflavin, thiamine propyl disulfide, vitamin B12, phytic acid, folic acid.
2, preparation method according to claim 1 is characterized in that additive effective concentration is respectively hydrolyzed casein 0.5-50 grams per liter, rice powder 0.5-50 grams per liter, millet powder 0.5-50 grams per liter, fructose 0.5-25 grams per liter, glucosamine 0.5-25 grams per liter, ferrous gluconate, 0.02-0.25 grams per liter, zinc chloride 0.01-0.9 grams per liter, ferrous citrate 0.01-0.9 grams per liter, iron lactate 0.01-0.9 grams per liter, Zinc Gluconate 0.01-0.9 grams per liter, ferric ammonium citrate 0.005-0.5 grams per liter, riboflavin 0.02-0.45 mg/litre, thiamine propyl disulfide 0.02-0.45 mg/litre, vitamin B12 0.02-0.45 mg/litre, phytic acid 0.01-0.5 mg/litre, folic acid 0.01-0.2 mg/litre.
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| CN1253579C CN1253579C (en) | 2006-04-26 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100441679C (en) * | 2006-11-24 | 2008-12-10 | 西安利能科技有限责任公司 | Bacterium composite nutrient |
| CN102154402A (en) * | 2010-12-22 | 2011-08-17 | 东辰控股集团有限公司 | Pre-fermentation seed culture method and feeding process for sodium hyaluronate |
| US8536106B2 (en) | 2010-04-14 | 2013-09-17 | Ecolab Usa Inc. | Ferric hydroxycarboxylate as a builder |
| CN103361345A (en) * | 2013-06-15 | 2013-10-23 | 福州大学 | Method for reinforcing biosynthesis of secondary metabolite by recombining and controlling biological components |
| CN111304129A (en) * | 2020-03-10 | 2020-06-19 | 福安药业集团烟台只楚药业有限公司 | Micromonospora purpurea mutant strain, preparation method and application in preparation of gentamicin sulfate |
-
2004
- 2004-02-12 CN CN 200410039137 patent/CN1253579C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100441679C (en) * | 2006-11-24 | 2008-12-10 | 西安利能科技有限责任公司 | Bacterium composite nutrient |
| US8536106B2 (en) | 2010-04-14 | 2013-09-17 | Ecolab Usa Inc. | Ferric hydroxycarboxylate as a builder |
| US9023780B2 (en) | 2010-04-14 | 2015-05-05 | Ecolab Usa Inc. | Ferric hydroxycarboxylate as a builder |
| CN102154402A (en) * | 2010-12-22 | 2011-08-17 | 东辰控股集团有限公司 | Pre-fermentation seed culture method and feeding process for sodium hyaluronate |
| CN103361345A (en) * | 2013-06-15 | 2013-10-23 | 福州大学 | Method for reinforcing biosynthesis of secondary metabolite by recombining and controlling biological components |
| CN111304129A (en) * | 2020-03-10 | 2020-06-19 | 福安药业集团烟台只楚药业有限公司 | Micromonospora purpurea mutant strain, preparation method and application in preparation of gentamicin sulfate |
| CN111304129B (en) * | 2020-03-10 | 2021-11-02 | 福安药业集团烟台只楚药业有限公司 | Micromonospora purpurea mutant strain, preparation method and application in preparation of gentamicin sulfate |
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| CN1253579C (en) | 2006-04-26 |
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Granted publication date: 20060426 Termination date: 20140212 |