CN101280336A - Screening method for low-oxygen-consumption producer strain of clavulanic acid - Google Patents
Screening method for low-oxygen-consumption producer strain of clavulanic acid Download PDFInfo
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Abstract
The utility model belongs to the biomedicine field, which discloses a screening method of low oxygen consumption clavulanic acid production strain. The invention comprises the steps of primary screening, secondary screening and mini type fermentation pot experimenting. The screening method of low oxygen consumption strain has the advantages that the operation is easy and convenient, the source of the related culture medium material is wide and the cost is low, and the method is very suitable for the requirement of industry production.
Description
Technical field
The invention belongs to biomedicine field, be specifically related to the screening method that a kind of low oxygen consumption clavulanic acid is produced bacterial strain.
Background technology
Because being extensive use of of penicillin, some bacterium has produced resistance to it.Penicillins and cephalosporins medicine all contain a common beta-lactam structure, belong to β-Nei Xiananleikangshengsu.When use had the microbiotic of this structure, the part pathogenic bacteria produced resistance by producing β-Nei Xiananmei.(clavulanic acid CA) claims clavulanic acid again to clavulanic acid, is a kind of efficient beta-lactamase inhibitor that clavuligerus (Streptomyces clavuligerus) produces.Clavulanic acid can improve the susceptibility of above-mentioned pathogenic bacteria to β-Nei Xiananleikangshengsu greatly.The anti-microbial activity of clavulanic acid itself is very weak, but it is brute force, wide spectrum and irreversible beta-lactamase inhibitor.No matter in external or body, can both generate firm irreversible binding substances with the β-Nei Xiananmei that drug-fast gram-positive microorganism and Gram-negative bacteria produced, thereby suppress the Decomposition of drug tolerant bacteria, recover penicillins and cephalosporins anti-microbial activity the drug tolerant bacteria of a lot of generation β-Nei Xiananmeis to β-Nei Xiananleikangshengsu.
From Bromn of Britain Beecham company in 1976 etc. had found natural beta-lactam inhibitor clavulanic acid first from the fermented liquid of clavuligerus (Streptomyces clavuligerusATCC27046) since, clavulanic acid had obtained using widely.In fermentative production, clavuligerus is had relatively high expectations to oxygen, the electric energy that higher mixing speed and air flow consumption are a large amount of and influence the growthhabit of mycelia.
During the fermentation, the energy expenditure of fermentor tank mainly is made up of following three parts: agitator motor power consumption, the preparation energy that feeds sterile air and substratum sterilization and cooling energy.Substratum sterilization and cooling energy depend primarily on technological process and strain properties, and power of agitator is identical with the purpose of sterile air consumed energy, mainly is in order to supply microorganism enough oxygen.Therefore, need during the fermentation constantly to feed sterile air to fermentation system, the stirring by fermentor tank further disperses, and makes the dissolved oxygen concentration that keeps appropriateness in the fermented liquid.For a long time, people only improve the dissolved oxygen of fermented liquid from strengthening air flow and this two aspect of mixing speed, improve fermentation unit.But, stir too intensely and can produce very big shearing force, cause the inactivation of microbial strains and product.In addition, power of agitator is excessive, also can cause system's operation uneconomical, causes the fermentation costs height.In the air flow scope of certain limit, Kla increases with the increase of air flow, but when surpassing certain limit, a large amount of gases can directly pass agitator without dispersion with the air pocket form buoyance lift that makes progress, " gas is general " phenomenon occurs, power of agitator can descend greatly, and Kla also no longer increases, blindly increasing air flow not necessarily just can increase dissolved oxygen, can increase the burden of air filter and the possibility of microbiological contamination on the contrary.During the fermentation, the air compressor machine air feed need consume a large amount of electric energy, accounts for 30%～70% of fermentative production total electricity consumption, and mechanical stirring also consumes a large amount of electric energy.In the fermentative production of clavulanic acid, clavuligerus is had relatively high expectations to oxygen, the electric energy that higher mixing speed and air flow consumption are a large amount of and influence the growthhabit of mycelia.Obviously, the oxygen-consumption of reduction clavuligerus bacterial classification can reduce the cost in the fermentative production effectively.
Summary of the invention
The present invention is by lot of experiments, and purpose is to provide for industrial production a kind of method of low oxygen consumption bacterial strain, and a kind of method that low oxygen consumption clavulanic acid is produced bacterial strain of screening specifically is provided.
A kind of low oxygen consumption clavulanic acid involved in the present invention is produced bacterium---the screening method of clavuligerus (Streptomycesclavuligerus) bacterial strain, comprises primary dcreening operation, multiple sieve and the test of small-sized fermentation jar.
(1) primary dcreening operation: the spore suspension of mutagenic treatment is suitably coated on the flat board after the dilution, in the hypoxemia incubator, cultivate, the restriction concentration of oxygen was cultivated 10-12 days for 28 ℃ between 15%-21%, selected growth and produced the good inoculation inclined-plane of spore, cultivated 10-12 days for 28 ℃, spore suspension is made after producing spore in the inclined-plane, and the inoculation seed shakes bottle, cultivates that inoculation fermentation shakes bottle after 20-40 hour for 28 ℃, cultivate to measure after 4 days for 28 ℃ and tire, pick out the higher bacterial strain of tiring;
(2) multiple sieve: the inoculation seed that will tire higher shakes bottle, and the rotating speed that reduces shaking table is cultivated after 40-48 hour for 28 ℃ to 50-100rpm, selects the good inoculation fermentation shake flask of mycelial growth, and the amount of oxygen in the bottle is shaken in control.Cultivate to measure after 4 days for 28 ℃ and tire;
(3) small-sized fermentation jar test: the higher bacterial strain of will tiring carries out the ferment tank test.Cultured bacterial classification in (2) is received in the fermentor tank, inoculum size is 5-10% (V/V), in temperature is 28 ℃, mixing speed is 300-600 rev/min, air flow 0.5VVM-1.2VVM (volume/volume/minute), tank pressure 0.05-0.08MPa, pH are 6.5-7.5, mend under the condition of nutrition material, cultivated 90-100 hour.
(1) used flat board and slant culture based component and content are in the step: glucose 4-10g/L, and malt extract 4-10g/L, yeast extract paste 4-10g/L, agar 20-25g/L, pH are 6.5-7.5.(1) used seed shake-flask culture based component and content is and in (2) step: peptone 3-10g/L, and malt extract 3-10g/L, yeast extract paste 3-10g/L, pH are 6.5-7.5.(1) used fermentation shake flask medium component and content is and in (2) step: glycerine 10-20g/L, analysis for soybean powder 20-30g/L, malt extract 10-20g/L, KH
2PO
41.0-3.5g/L, MgSO
47H
2O 0.5%-1.5g/L, FeSO
47H
2O 0.0005-0.0015g/L, MnCl
24H
2O 0.0005-0.0015g/L, ZnSO
47H
2O 0.0005-0.0015g/L, MOPS 10-20g/L, pH are 6.5-7.5.(3) used fermentation culture based component and content is in the step: glycerine 10-20g/L, cottonseed meal 40-60g/L, starch 10-20g/L, KH
2PO
41.0-3.5g/L, MgSO
47H
2O 0.5%-2.5g/L, FeSO
47H
2O0.005-0.035g/L, MnCl
24H
2O 0.005-0.015g/L, ZnSO
47H
2O 0.005-0.045g/L, defoamer 2-5g/L, pH are 6.5-7.5.
The method of the low oxygen consumption bacterial strain of screening provided by the present invention is easy to operation, and related culture medium raw material source is wide, and cost is low, is fit to very much industrial needs.Prior, in the present invention, the bacterial strain of the low oxygen consumption of screening can reduce oxygen-consumption, reduces mixing speed and air flow effectively, reduces with the electric weight in the fermentation, reduces the cost in the fermentative production.
Embodiment
Embodiment 1
Mutagenesis: clavuligerus (Streptomyces clavuligerus) spore suspension is passed through NTG mutagenesis.
Primary dcreening operation: according to following formulated plate culture medium 3.5L: glucose 8g/L, malt extract 6g/L, yeast extract paste 4g/L, agar 25g/L, pH are 7.2.Prepare 100 of sterile petri dish.Pour into behind the medium sterilization and make flat board in the culture dish.Spore suspension that will mutagenic treatment suitably be coated on the flat board after the dilution, cultivate in oxygen concentration is 16% three gas incubators, cultivate 10-12 days for 28 ℃.According to following formulated slant medium 4L: glucose 8g/L, malt extract 6g/L, yeast extract paste 4g/L, agar 25g/L, pH are 7.2.Prepare 200 in test tube, bevel is standby.Select in the flat board growth and produce the good inoculation inclined-plane of spore, cultivate in oxygen concentration is 16% three gas incubators, cultivated 10-12 days for 28 ℃, spore suspension is made after producing spore in the inclined-plane, and the inoculation seed shakes bottle.Seed shake-flask culture based component and content are: peptone 3g/L, and malt extract 8g/L, yeast extract paste 5g/L, pH are 7.2.Cultivate that inoculation fermentation shakes bottle after 20-40 hour for 28 ℃.Fermentation shake flask medium component and content are: glycerine 15g/L, analysis for soybean powder 25g/L, malt extract 15g/L, KH
2PO
42.5g/L, MgSO
47H
2O 0.75g/L, FeSO
47H
2O 0.001g/L, MnCl
24H
2O 0.001g/L, ZnSO
47H
2O0.001g/L, MOPS 20g/L, pH are 7.1.Cultivate to measure after 4 days for 28 ℃ and tire, pick out 3 of the higher bacterial strains of tiring.Repeat above process 44 times.The bacterial strain that at every turn filters out is preserved.
Multiple sieve: the inoculation seed that will tire higher shakes bottle, and the rotating speed of control shaking table is 60rpm, cultivates after 40-48 hour for 28 ℃, and inoculation fermentation shakes bottle, and the rotating speed of control shaking table is 60rpm, cultivates to measure after 4 days for 28 ℃ and tires.Select 3 of the higher bacterial strains of tiring, preserve, standby.
The test of small-sized fermentation jar: the bacterial strain NTGM0702 that will tire higher carries out the ferment tank test.Press following formulated seed shake-flask culture base 1.4L: peptone 3g/L, malt extract 8g/L, yeast extract paste 5g/L, pH are 7.2.Substratum is packed in 7 2L triangular flasks into every bottle of 200mL.2 milliliters of sterilization back inoculating spores suspension are cultivated after 40 hours for 28 ℃, choose the seed of 5 bottles of well-growns and the assorted bacterium of nothing, and bottle, and are standby.Use 15L small-sized fermentation jar to carry out fermentation test.According to following formulated fermention medium 10L: glycerine 15g/L, cottonseed meal 45g/L, malt extract 15g/L, KH
2PO
42.5g/L, MgSO
47H
2O 0.75g/L, FeSO
47H
2O 0.01g/L, MnCl
24H
2O 0.01g/L, ZnSO
47H
2O 0.01g/L, defoamer 4g/L, pH are 7.1.Join back volume 7.6L, the back volume that disappears in fact is 9L.Shake-flask seed is inoculated in 15 liters of fermentor tanks, and inoculum size is 10% (V/V).Initial condition are that 28 ℃ of temperature, rotating speed 300rpm, air flow are 0.5VVM, tank pressure 0.05MPa.During the fermentation, dissolved oxygen is maintained more than 30%.Mixing speed is 300-550 rev/min, air flow 0.5VVM-1.1VVM (volume/volume/minute), tank pressure 0.05-0.07MPa, pH are 6.9-7.4, mend under the condition of nutrition material, cultivate 110 hours.The bacterial strain picked out is carried out the test of small-sized fermentation jar by as above step respectively, mixing speed, air flow, OUR and tiring etc. comprehensively compared, filter out few and 1 of the high bacterial strain of tiring of oxygen consumption.
Embodiment 2
Mutagenesis: clavuligerus (Streptomyces clavuligerus) spore suspension is passed through ultraviolet mutagenesis.
Primary dcreening operation: according to following formulated plate culture medium 3.5L: glucose 8g/L, malt extract 5g/L, yeast extract paste 4g/L, agar 24g/L, pH are 7.2.Prepare 100 of sterile petri dish.Pour into behind the medium sterilization and make flat board in the culture dish.Spore suspension that will mutagenic treatment suitably be coated on the flat board after the dilution, cultivate in oxygen concentration is 18% three gas incubators, cultivate 10-12 days for 28 ℃.According to following formulated slant medium 4L: glucose 8g/L, malt extract 5g/L, yeast extract paste 4g/L, agar 25g/L, pH are 7.2.Prepare 200 in test tube, bevel is standby.Select in the flat board growth and produce the good inoculation inclined-plane of spore, cultivate in oxygen concentration is 18% three gas incubators, cultivated 10-12 days for 28 ℃, spore suspension is made after producing spore in the inclined-plane, and the inoculation seed shakes bottle.Seed shake-flask culture based component and content are: peptone 3g/L, and malt extract 7g/L, yeast extract paste 5g/L, pH are 7.2.Cultivate that inoculation fermentation shakes bottle after 20-40 hour for 28 ℃.Fermentation shake flask medium component and content are: glycerine 15g/L, analysis for soybean powder 25g/L, malt extract 15g/L, KH
2PO
42.5g/L, MgSO
47H
2O 0.75g/L, FeSO
47H
2O 0.001g/L, MnCl
24H
2O 0.001g/L, ZnSO
47H
2O0.001g/L, MOPS 20g/L, pH are 7.1.Cultivate to measure after 4 days for 28 ℃ and tire, pick out 2 of the higher bacterial strains of tiring.Repeat above process 34 times.The bacterial strain that at every turn filters out is preserved.
Multiple sieve: the inoculation seed that will tire higher shakes bottle, and the rotating speed of control shaking table is 70rpm, cultivates after 40-48 hour for 28 ℃, and inoculation fermentation shakes bottle, and the rotating speed of control shaking table is 70rpm, cultivates to measure after 4 days for 28 ℃ and tires.Select 3 of the higher bacterial strains of tiring, preserve, standby.
The test of small-sized fermentation jar: the bacterial strain ZWM0603 that will tire higher carries out the ferment tank test.Press following formulated seed shake-flask culture base 1.4L: peptone 3g/L, malt extract 8g/L, yeast extract paste 5g/L, pH are 7.2.Substratum is packed in 7 2L triangular flasks into every bottle of 200mL.2 milliliters of sterilization back inoculating spores suspension are cultivated after 40 hours for 28 ℃, choose the seed of 5 bottles of well-growns and the assorted bacterium of nothing, and bottle, and are standby.Use 15L small-sized fermentation jar to carry out fermentation test.According to following formulated fermention medium 10L: glycerine 15g/L, cottonseed meal 45g/L, malt extract 15g/L, KH
2PO
42.5g/L, MgSO
47H
2O 0.75g/L, FeSO
47H
2O 0.01g/L, MnCl
24H
2O 0.01g/L, ZnSO
47H
2O 0.01g/L, defoamer 4g/L, pH are 7.1.Join back volume 7.5L, the back volume that disappears in fact is 9L.Shake-flask seed is inoculated in 15 liters of fermentor tanks, and inoculum size is 10% (V/V), and initial condition are that 28 ℃ of temperature, rotating speed 300rpm, air flow are 0.5VVM, tank pressure 0.05MPa.During the fermentation, dissolved oxygen is maintained more than 30%.Mixing speed is 300-530 rev/min, air flow 0.5VVM-1.2VVM (volume/volume/minute), tank pressure 0.05-0.07MPa, pH are 6.9-7.4, mend under the condition of nutrition material, cultivate 110 hours.The bacterial strain picked out is carried out the test of small-sized fermentation jar by as above step respectively, mixing speed, air flow, OUR and tiring etc. comprehensively compared, filter out few and 1 of the high bacterial strain of tiring of oxygen consumption.
Embodiment 3
Mutagenesis: clavuligerus (Streptomyces clavuligerus) spore suspension is passed through microwave irradiation.
Primary dcreening operation: according to following formulated plate culture medium 3.5L: glucose 8g/L, malt extract 6g/L, yeast extract paste 4g/L, agar 25g/L, pH are 7.2.Prepare 100 of sterile petri dish.Pour into behind the medium sterilization and make flat board in the culture dish.Spore suspension that will mutagenic treatment suitably be coated on the flat board after the dilution, cultivate in oxygen concentration is 16% three gas incubators, cultivate 10-12 days for 28 ℃.According to following formulated slant medium 4L: glucose 8g/L, malt extract 6g/L, yeast extract paste 4g/L, agar 25g/L, pH are 7.2.Prepare 200 in test tube, bevel is standby.Select in the flat board growth and produce the good inoculation inclined-plane of spore, cultivate in oxygen concentration is 17% three gas incubators, cultivated 10-12 days for 28 ℃, spore suspension is made after producing spore in the inclined-plane, and the inoculation seed shakes bottle.Seed shake-flask culture based component and content are: peptone 3g/L, and malt extract 8g/L, yeast extract paste 5g/L, pH are 7.2.Cultivate that inoculation fermentation shakes bottle after 20-40 hour for 28 ℃.Fermentation shake flask medium component and content are: glycerine 15g/L, analysis for soybean powder 25g/L, malt extract 15g/L, KH
2PO
42.5g/L, MgSO
47H
2O 0.75g/L, FeSO
47H
2O 0.001g/L, MnCl
24H
2O 0.001g/L, ZnSO
47H
2O0.001g/L, MOPS 20g/L, pH are 7.1.Cultivate to measure after 4 days for 28 ℃ and tire, pick out 2 of the higher bacterial strains of tiring.Repeat above process 28 times.The bacterial strain that at every turn filters out is preserved.
Multiple sieve: the inoculation seed that will tire higher shakes bottle, and the rotating speed of control shaking table is 60rpm, cultivates after 40-48 hour for 28 ℃, and inoculation fermentation shakes bottle, and the rotating speed of control shaking table is 80rpm, cultivates to measure after 4 days for 28 ℃ and tires.Select 3 of the higher bacterial strains of tiring, preserve, standby.
The test of small-sized fermentation jar: the bacterial strain WBM0703 that will tire higher carries out the ferment tank test.Press following formulated seed shake-flask culture base 1.4L: peptone 3g/L, malt extract 8g/L, yeast extract paste 5g/L, pH are 7.2.Substratum is packed in 7 2L triangular flasks into every bottle of 200mL.2 milliliters of sterilization back inoculating spores suspension are cultivated after 40 hours for 28 ℃, choose the seed of 5 bottles of well-growns and the assorted bacterium of nothing, and bottle, and are standby.Use 15L small-sized fermentation jar to carry out fermentation test.According to following formulated fermention medium 10L: glycerine 15g/L, cottonseed meal 45g/L, malt extract 15g/L, KH
2PO
42.5g/L, MgSO
47H
2O 0.75g/L, FeSO
47H
2O 0.01g/L, MnCl
24H
2O 0.01g/L, ZnSO
47H
2O 0.01g/L, defoamer 4g/L, pH are 7.1.Join back volume 7.6L, the back volume that disappears in fact is 9L.Shake-flask seed is inoculated in 15 liters of fermentor tanks, and inoculum size is 10% (V/V).Initial condition are that 28 ℃ of temperature, rotating speed 300rpm, air flow are 0.5VVM, tank pressure 0.05MPa.During the fermentation, dissolved oxygen is maintained more than 30%.Mixing speed is 300-530 rev/min, air flow 0.5VVM-1.1VVM (volume/volume/minute), tank pressure 0.05-0.07MPa, pH are 6.9-7.4, mend under the condition of nutrition material, cultivate 110 hours.The bacterial strain picked out is carried out the test of small-sized fermentation jar by as above step respectively, mixing speed, air flow, OUR and tiring etc. comprehensively compared, filter out few and 1 of the high bacterial strain of tiring of oxygen consumption.
Claims (5)
1. the screening method of one kind low oxygen consumption clavulanic acid production bacterial strain comprises the steps:
(1) primary dcreening operation: the spore suspension of mutagenic treatment is suitably coated on the flat board after the dilution, in the hypoxemia incubator, cultivate, the restriction concentration of oxygen was cultivated 10-12 days for 28 ℃ between 15%-21%, selected growth and produced the good inoculation inclined-plane of spore, cultivated 10-12 days for 28 ℃, spore suspension is made after producing spore in the inclined-plane, and the inoculation seed shakes bottle, cultivates that inoculation fermentation shakes bottle after 20-40 hour for 28 ℃, cultivate to measure after 4 days for 28 ℃ and tire, pick out the higher bacterial strain of tiring;
(2) multiple sieve: the inoculation seed that will tire higher shakes bottle, the rotating speed that reduces shaking table is cultivated after 40-48 hour, is selected the good inoculation fermentation shake flask of mycelial growth for 28 ℃ to 50-100rpm, the amount of oxygen in the bottle is shaken in control, cultivates to measure after 4 days for 28 ℃ and tires;
(3) small-sized fermentation jar test: the higher bacterial strain of will tiring carries out the ferment tank test, cultured bacterial classification in (2) is received in the fermentor tank, inoculum size is 5-10% (volume percent), in temperature is 28 ℃, and mixing speed is 300-600 rev/min, air flow 0.5VVM-1.2VVM (volume/volume/minute), tank pressure 0.05-0.08MPa, pH is 6.5-7.5, mends under the condition of nutrition material, cultivates 90-100 hour.
2. method according to claim 1 is characterized in that used flat board and slant culture based component and content are in described (1) step: glucose 4-10g/L, and malt extract 4-10g/L, yeast extract paste 4-10g/L, agar 20-25g/L, pH are 6.5-7.5.
3. method according to claim 1 is characterized in that seed shake-flask culture based component and content used in described (1) or (2) step are: peptone 3-10g/L, and malt extract 3-10g/L, yeast extract paste 3-10g/L, pH are 6.5-7.5.
4. method according to claim 1 is characterized in that fermentation shake flask medium component and content used in described (1) and (2) step are: glycerine 10-20g/L, analysis for soybean powder 20-30g/L, malt extract 10-20g/L, KH
2PO
41.0-3.5g/L, MgSO
47H
2O 0.5%-1.5g/L, FeSO
47H
2O 0.0005-0.0015g/L, MnCl
24H
2O0.0005-0.0015g/L, ZnSO
47H
2O 0.0005-0.0015g/L, MOPS 10-20g/L, pH are 6.5-7.5.
5. method according to claim 1 is characterized in that fermentation culture based component and content used in described (3) step are: glycerine 10-20g/L, analysis for soybean powder 40-60g/L, malt extract 10-20g/L, KH
2PO
41.0-3.5g/L, MgSO
47H
2O 0.5%-2.5g/L, FeSO
47H
2O 0.005-0.035g/L, MnCl
24H
2O 0.005-0.015g/L, ZnSO
47H
2O 0.005-0.045g/L, defoamer 2-5g/L, pH are 6.5-7.5.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103468607A (en) * | 2013-08-20 | 2013-12-25 | 中国科学院微生物研究所 | Streptomyces clavuligerus for high-yield clavulanic acid and application of streptomyces clavuligerus |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103468607A (en) * | 2013-08-20 | 2013-12-25 | 中国科学院微生物研究所 | Streptomyces clavuligerus for high-yield clavulanic acid and application of streptomyces clavuligerus |
| CN103468607B (en) * | 2013-08-20 | 2015-04-08 | 中国科学院微生物研究所 | Streptomyces clavuligerus for high-yield clavulanic acid and application of streptomyces clavuligerus |
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Assignee: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2010370000510 Denomination of invention: Screening method for low-oxygen-consumption producer strain of clavulanic acid Granted publication date: 20090923 License type: Exclusive License Open date: 20081008 Record date: 20100908 |
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Assignee: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2010370000510 Date of cancellation: 20121226 |
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Application publication date: 20081008 Assignee: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2013370000264 Denomination of invention: Screening method for low-oxygen-consumption producer strain of clavulanic acid Granted publication date: 20090923 License type: Exclusive License Record date: 20131210 |
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