CN102250872A - Method for breeding high-yield ascomycin strain by performing femtosecond laser mutagenesis on streptomyces hygroscopicus ascomycota subspecies and culture medium preparation - Google Patents
Method for breeding high-yield ascomycin strain by performing femtosecond laser mutagenesis on streptomyces hygroscopicus ascomycota subspecies and culture medium preparation Download PDFInfo
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Abstract
The invention discloses a method for breeding an high-yield ascomycin strain by performing femtosecond laser mutagenesis on streptomyces hygroscopicus ascomycota subspecies and a culture medium preparation method; the method comprises the following steps: at room temperature, mixing mature slant spores of the streptomyces hygroscopicus ascomycota subspecies (ATCC14891) and sterile water to obtain monospore suspension containing 106-107 spores per milliliter; irradiating the spore suspension for 1-10 min by using the titanium sapphire femtosecond laser with centre wavelength of 800 nm, pulse width of 150 fs and frequency of 76 MHz under a irradiation power of 10-30m W; properly diluting the spore suspension, coating on a solid panel to culture, then screening by using a shake flask to obtain a high-yield ascomycin mutation strain. The method provided by the invention has the advantages that the used femtosecond laser mutagenesis method is feasible and safe to operate; the mutation effect is better than that of the traditional physical and chemical mutagenesis method, and the femtosecond laser mutagenesis method has great popularization value in breeding of microorganism pharmaceutical strains; by using the femtosecond laser irradiation to perform the mutagenesis, the high-yield ascomycin mutation strain can be bred. The positive mutation rate of the mutation strain is 5-30%, and fermenting unit is improved by 10-60% in comparison with that of an original strain.
Description
Technical field
The invention belongs to microbial technology field, particularly femtosecond laser mutagenesis streptomyces hygroscopicus ascus subspecies seed selection ascosin superior strain method and medium preparation.
Background technology
Macrolide immunosuppressants is one group of new immunosuppressor with macrolide structure, studies have shown that to have tangible immunosuppressive action through the inside and outside, comprising ascosin (ascomycin, FK-520) and derivative.Ascosin is to be separated from the soil that contains streptomyces hygroscopicus (Streptomyces hygroscopicus No.KK317) by Japanese rattan pool drugmaker to obtain.It is that (tacrolimus, ethyl analogue FK-506) can be used for treating autoimmune disorder, dermatosis and prevention of organ transplant rejection to the immunosuppressor tacrolimus.In addition, a series of ascosins that studies show that also have anti-malarial, neuroprotective and regeneration, spasmolytic isoreactivity.
Ascosin mainly is to be used for antibiotic purpose at the beginning of finding, after the analog tacrolimus of finding it has immunosuppressive activity, has promoted the research of the immunosuppressive activity of ascosin and derivative thereof rapidly.Pimecrolimus (pimecrolimus, SDZ-ASM981) be the chlorine derivative of ascosin, trade(brand)name Elidel, develop by Switzerland Novartis Co.,Ltd, calendar year 2001 is used for the children or the light moderate atopic dermatitis of being grown up more than 2 years old by food and drug administration (FDA) approval 1% pimecrolimus emulsifiable paste, at first goes on the market in Britain in 2002.Be the non-steroidal drug of treatment atopic dermatitis getting up early alleviation and long-term control, discovered in recent years can be used for treating vitiligo, and it is about to enter clinical trial as treatment gastrointestinal tract inflammation medicine.Because a lot of clinical advantages is arranged, since ascosin and the pimecrolimus listing, the market share rises rapidly.It is reported, the market price of the ascosin U.S. in 2006 is 150000 dollars/Kg, the market price of its derivative " pimecrolimus " is 500000 dollars/Kg, and pimecrolimus reaches 159248000 dollars in the sales volume of the U.S., and its using value and marketable value receive much concern.
2007, India scholar Parveen etc. applies for a patent the unit that WO2007/029082 reported ascosin and reaches 350-400mg/L, but domestic research to ascosin also is in the starting stage, and fermentation unit is generally at 150-200mg/L, compare with external fermentation titer, bigger gap is arranged.So gap is that domestic bacterial strain prepares a little less than the ability of ascosin after all, and usefulness is low.Also there is not the report of ascosin suitability for industrialized production in China at present, and its market is captured by offshore companies such as Japan, Switzerland and the U.S. substantially.The ascosin high yield bacterium that exploitation has independent intellectual property right is broken the monopoly position of developed country in this field, has urgent realistic meaning and using value.
The application of mutation induced by laser technology in microorganism mutation breeding is comparatively extensive, and most researchers all adopts the low power visible laser to carry out the research of biological induced-mutation breeding at present.It is undesirable that but traditional lower powered visible laser mutagenesis means continue the throughput effect of raising sudden change bacterial classification, and have defectives such as easy damaged cells activity, mutation efficiency are low, must adopt novel femtosecond laser selection by mutation technology to carry out the research of bacterial classification renovation technique.Femtosecond laser is because the pulse duration is short, momentary power is big, focal dimension is little, makes it in field of biology wide application prospect be arranged.A wherein most important direction is the application of femtosecond laser induced-mutation technique aspect biomass cells, cell is the fundamental unit of all organisms, so use the femtosecond laser induced-mutation technique in streptomyces hygroscopicus ascus subspecies, can reach a series of key enzyme activity enhanced purposes, improve the throughput of streptomyces hygroscopicus ascus subspecies.Though have the part scholar to use the research that infrared femtosecond laser has carried out light and organism effect at present, mostly be engaged in the applied research of medical science aspects such as the detection of medical science imaging and living organisms, surgery medical treatment.University Of Tianjin hears Jianping seminar and utilizes femtosecond laser mutagenesis Rhizopus oryzae (to hear the Jianping, Yu Shouzhi. the method for femtosecond laser mutagenesis Rhizopus oryzae seed selection fumaric acid superior strain, CN102061294A), obtained good effect, yet femtosecond laser is applied in the seed selection aspect of producing the ascosin bacterial classification, does not see relevant patent and bibliographical information.
Summary of the invention
The objective of the invention is to propose the method for a kind of femtosecond laser mutagenesis streptomyces hygroscopicus and seed selection ascosin superior strain, the bacterial classification of Using such method mutagenesis can improve the output of ascosin effectively.
The present invention is achieved through the following technical solutions: the present invention carries out mutagenesis to the original bacterium of preparation ascosin, and this original bacterium is streptomyces hygroscopicus ascus subspecies (Streptomyces hygroscopicus var.ascomyceticus).The feature of this induction mutation of bacterium method comprises following process: at room temperature, get ripe spore inclined-plane and add an amount of sterilized water, the spore that agar is shown scrapes gently, this spore suspension is placed in the 50ml triangular flask of sterilizing, place several aseptic glass spheres in advance in the bottle, absorbent cotton with sterilization behind the shake well filters, and with aseptic water washing filter residue 2-3 time, makes 10
6-10
7The monospore suspension of individual/ml, the suspension of 0.2ml is sub-packed in the centrifuge tube of aseptic 1.5ml, the titanium jewel femtosecond laser that adopts centre wavelength 800nm, pulsewidth 150fs, frequency 76MHz is under irradiation power 10-30mW, to this spore irradiation 1-10min, then through the spore suspension of radiation treatment through 10 times of gradient dilutions 10 of sterilized water
3-10
4Doubly, getting spore liquid 0.1ml after the dilution coats in the solid plate substratum 28 ℃ and cultivated 10 days, choose well-grown single strain and be inoculated in 28 ℃ of cultivations of slant medium 10 days, taking fresh spore inclined-plane shakes in the bottle in the 250ml that the 40ml seed culture medium is housed, 28 ℃, cultivate 48h in the 200rpm shaking table, back 10% (v/v) is inoculated in the 250ml that the 40ml fermention medium is housed and shakes in the bottle, 26 ℃-30 ℃, cultivate 144-192h in the 180-220rpm shaking table, HPLC detects ascosin content, therefrom obtains the inheritance stability of mutagenesis, the pure bacterium streptomyces hygroscopicus ascus subspecies that fermentation unit improves.
Described solid and slant medium are formed and content is: soyflour 15-25g/L, N.F,USP MANNITOL 15-25g/L, agar 18-22g/L, initial pH7.0; The seed liquor substratum is formed and content is: starch 8-12g/L, glucose 25-35g/L, peptone 5-7g/L, yeast powder 5-7g/L, lime carbonate 1-3g/L, initial pH7.0; Starch 15-25g/L, dextrin 35-45g/L, seitan powder 2-3g/L, peptone 4-6g/L, yeast powder 8-12g/L, corn steep liquor 4-6g/L, cold press soybean cake powder 4-6g/L, dipotassium hydrogen phosphate 0.5-1.5g/L, ammonium sulfate 0.5-1.5g/L, sal epsom 0.5-1.5g/L, lime carbonate 0.5-1.5g/L, initial pH7.0.
Advantage of the present invention shows as: adopt the mode of titanium jewel femtosecond laser irradiation to carry out the bacterial classification that produces ascosin is carried out femtosecond laser mutagenesis, femtosecond laser mutagenesis have the burst length short, momentary power is big, focal dimension is little, efficiency of inducing mutation is high, the unsuitable active characteristics of damaging cells, its mutagenesis effect is good far beyond traditional mutation induced by laser methods such as He-Ne, and bigger promotional value is arranged in the microbiological pharmacy strain improvement.The present invention carries out mutagenesis by utilizing the femtosecond laser irradiation, can select the streptomyces hygroscopicus ascus subspecies mutant strain of high yield ascosin.Mutant strain positive mutation rate 5-30%.Fermentation unit is compared with original strain, has improved 10-60%.
Embodiment
Embodiment 1
At room temperature, (ascomycin, FK-520) ripe spore inclined-plane adds an amount of sterilized water, makes 10 to get ascosin
6-10
7The monospore suspension of individual/ml is sub-packed in the suspension of 0.2ml in the centrifuge tube of aseptic 1.5ml, carries out femtosecond laser (centre wavelength 800nm, pulsewidth 150fs, frequency 76MHz) irradiation 10min, irradiation power 10mW.Spore suspension after the radiation treatment is through 10 times of gradient dilutions 10 of sterilized water
3-10
4Doubly the back is drawn 0.1ml and is coated solid plate substratum (soyflour 15g/L, N.F,USP MANNITOL 15g/L, agar 20g/L, pH7.0) 28 lucifuges were cultivated 10 days in, choose well-grown single strain and be inoculated in slant medium (soyflour 20g/L, N.F,USP MANNITOL 15g/L, agar 20g/L, pH7.0) cultivated 10 days for 28 ℃, take fresh spore inclined-plane in 40ml seed culture medium (starch 8g/L is housed, glucose 35g/L, peptone 6g/L, yeast powder 7g/L, lime carbonate 1.5g/L, initial pH7.0) 250ml shakes in the bottle, 28 ℃, cultivate 48h in the 200rpm shaking table, back 10% (v/v) is inoculated in 40ml fermention medium (starch 22g/L is housed, dextrin 45g/L, seitan powder 2g/L, peptone 4g/L, yeast powder 11g/L, corn steep liquor 4g/L, cold press soybean cake powder 4g/L, dipotassium hydrogen phosphate 1g/L, ammonium sulfate 1g/L, sal epsom 0.5g/L, lime carbonate 1.5g/L, initial pH7.0) 250ml shakes in the bottle, 30 ℃, cultivate 180h in the 220rpm shaking table, HPLC detects ascosin content, selects the inheritance stability mutant strain of high yield ascosin.Mutant strain positive mutation rate 10-13%.Fermentation unit improves 10-15% than original strain.Adopt the mode of titanium jewel femtosecond laser irradiation to carry out the bacterial classification that produces ascosin is carried out femtosecond laser mutagenesis, femtosecond laser mutagenesis have the burst length short, momentary power is big, focal dimension is little, efficiency of inducing mutation is high, unsuitable damaging cells activity.
Embodiment 2
At room temperature, get ripe spore inclined-plane and add an amount of sterilized water, make 10
6-10
7The monospore suspension of individual/ml is sub-packed in the suspension of 0.2ml in the centrifuge tube of aseptic 1.5ml, carries out femtosecond laser (centre wavelength 800nm, pulsewidth 150fs, frequency 76MHz) irradiation 8min, irradiation power 15mW.Spore suspension after the radiation treatment is through 10 times of gradient dilutions 10 of sterilized water
3-10
4Doubly the back is drawn 0.1ml and is coated (soyflour 25g/L in the solid plate substratum, N.F,USP MANNITOL 15g/L, agar 20g/L, pH7.0) 28 ℃ of lucifuges were cultivated 10 days, choose well-grown single strain and be inoculated in slant medium (soyflour 15g/L, N.F,USP MANNITOL 22g/L, agar 22g/L, pH7.0) cultivated 10 days for 28 ℃, take fresh spore inclined-plane in 40ml seed culture medium (starch 10g/L is housed, glucose 32g/L, peptone 7g/L, yeast powder 7g/L, lime carbonate 3g/L, initial pH7.0) 250ml shakes in the bottle, 28 ℃, cultivate 48h in the 200rpm shaking table, back 10% (v/v) is inoculated in 40ml fermention medium (starch 20g/L is housed, dextrin 45g/L, seitan powder 2g/L, peptone 4g/L, yeast powder 8g/L, corn steep liquor 4g/L, cold press soybean cake powder 4g/L, dipotassium hydrogen phosphate 1.5g/L, ammonium sulfate 1g/L, sal epsom 1g/L, lime carbonate 1g/L, initial pH7.0) 250ml shakes in the bottle, 26 ℃, cultivate 192h in the 220rpm shaking table, HPLC detects ascosin content, selects the inheritance stability mutant strain of high yield ascosin.Mutant strain positive mutation rate 15-17%.Fermentation unit improves 35-42% than original strain.
Embodiment 3
At room temperature, get ripe spore inclined-plane and add an amount of sterilized water, make 10
6-10
7The monospore suspension of individual/ml is sub-packed in the suspension of 0.2ml in the centrifuge tube of aseptic 1.5ml, carries out femtosecond laser (centre wavelength 800nm, pulsewidth 150fs, frequency 76MHz) irradiation 6min, irradiation power 20mW.Spore suspension after the radiation treatment is through 10 times of gradient dilutions 10 of sterilized water
3-10
4Doubly the back is drawn 0.1ml and is coated solid plate substratum (soyflour 20g/L, N.F,USP MANNITOL 20g/L, agar 20g/L, pH7.0) 28 ℃ of lucifuges were cultivated 10 days in, choose well-grown single strain and be inoculated in slant medium (soyflour 22g/L, N.F,USP MANNITOL 22g/L, agar 20g/L, pH7.0) cultivated 10 days for 28 ℃, take fresh spore inclined-plane in 40ml seed culture medium (starch 10g/L is housed, glucose 30g/L, peptone 6g/L, yeast powder 6g/L, lime carbonate 2g/L, initial pH7.0) 250ml shakes in the bottle, 28 ℃, cultivate 48h in the 200rpm shaking table, back 10% (v/v) is inoculated in 40ml fermention medium (starch 15g/L is housed, dextrin 45g/L, seitan powder 3g/L, peptone 4g/L, yeast powder 12g/L, corn steep liquor 4g/L, cold press soybean cake powder 4g/L, dipotassium hydrogen phosphate 1.5g/L, ammonium sulfate 0.5g/L, sal epsom 1g/L, lime carbonate 1.5g/L, initial pH7.0) 250ml shakes in the bottle, 28 ℃, cultivate 168h in the 200rpm shaking table, HPLC detects ascosin content, selects the inheritance stability mutant strain of high yield ascosin.Mutant strain positive mutation rate 20-21%.Fermentation unit improves 48-52% than original strain.
Embodiment 4
At room temperature, get ripe spore inclined-plane and add an amount of sterilized water, make 10
6-10
7The monospore suspension of individual/ml is sub-packed in the suspension of 0.2ml in the centrifuge tube of aseptic 1.5ml, carries out femtosecond laser (centre wavelength 800nm, pulsewidth 150fs, frequency 76MHz) irradiation 4min, irradiation power 20mW.Spore suspension after the radiation treatment is through 10 times of gradient dilutions 10 of sterilized water
3-10
4Doubly the back is drawn 0.1ml and is coated solid plate substratum (soyflour 20g/L, N.F,USP MANNITOL 20g/L, agar 20g/L, pH7.0) 28 ℃ of lucifuges were cultivated 10 days in, choose well-grown single strain and be inoculated in slant medium (soyflour 15g/L, N.F,USP MANNITOL 25g/L, agar 20g/L, pH7.0) cultivated 10 days for 28 ℃, take fresh spore inclined-plane in 40ml seed culture medium (starch 10g/L is housed, glucose 30g/L, peptone 6g/L, yeast powder 6g/L, lime carbonate 2g/L, initial pH7.0) 250ml shakes in the bottle, 28 ℃, cultivate 48h in the 200rpm shaking table, back 10% (v/v) is inoculated in 40ml fermention medium (starch 20g/L is housed, dextrin 40g/L, seitan powder 2.5g/L, peptone 5g/L, yeast powder 10g/L, corn steep liquor 5g/L, cold press soybean cake powder 5g/L, dipotassium hydrogen phosphate 1g/L, ammonium sulfate 1g/L, sal epsom 1g/L, lime carbonate 1g/L, initial pH7.0) 250ml shakes in the bottle, 28 ℃, cultivate 168h in the 220rpm shaking table, HPLC detects ascosin content, selects the inheritance stability mutant strain of high yield ascosin.Mutant strain positive mutation rate 24-25%.Fermentation unit improves 55-58% than original strain.
Embodiment 5
At room temperature, get ripe spore inclined-plane and add an amount of sterilized water, make 10
6-10
7The monospore suspension of individual/ml is sub-packed in the suspension of 0.2ml in the centrifuge tube of aseptic 1.5ml, carries out femtosecond laser (centre wavelength 800nm, pulsewidth 150fs, frequency 76MHz) irradiation 2min, irradiation power 25mW.Spore suspension after the radiation treatment is through 10 times of gradient dilutions 10 of sterilized water
3-10
4Doubly the back is drawn 0.1ml and is coated solid plate substratum (soyflour 20g/L, N.F,USP MANNITOL 20g/L, agar 20g/L, pH7.0) 28 ℃ of lucifuges were cultivated 10 days in, choose well-grown single strain and be inoculated in slant medium (soyflour 20g/L, N.F,USP MANNITOL 20g/L, agar 20g/L, pH7.0) cultivated 10 days for 28 ℃, take fresh spore inclined-plane in 40ml seed culture medium (starch 10g/L is housed, glucose 30g/L, peptone 6g/L, yeast powder 6g/L, lime carbonate 2g/L, initial pH7.0) 250ml shakes in the bottle, 28 ℃, cultivate 48h in the 200rpm shaking table, back 10% (v/v) is inoculated in 40ml fermention medium (starch 20g/L is housed, dextrin 40g/L, seitan powder 2g/L, peptone 4g/L, yeast powder 8g/L, corn steep liquor 4g/L, cold press soybean cake powder 4g/L, dipotassium hydrogen phosphate 0.5g/L, ammonium sulfate 1.5g/L, sal epsom 1g/L, lime carbonate 0.5g/L, initial pH7.0), 26 ℃, cultivate 144h in the 180rpm shaking table, HPLC detects ascosin content, selects the inheritance stability mutant strain of high yield ascosin.Mutant strain positive mutation rate 18-20%.Fermentation unit improves 25-30% than original strain.
Embodiment 6
At room temperature, get ripe spore inclined-plane and add an amount of sterilized water, make 10
6-10
7The monospore suspension of individual/ml is sub-packed in the suspension of 0.2ml in the centrifuge tube of aseptic 1.5ml, carries out femtosecond laser (centre wavelength 800nm, pulsewidth 150fs, frequency 76MHz) irradiation 1min, irradiation power 30mW.Spore suspension after the radiation treatment is through 10 times of gradient dilutions 10 of sterilized water
3-10
4Doubly the back is drawn 0.1ml and is coated solid plate substratum (soyflour 20g/L, N.F,USP MANNITOL 20g/L, agar 20g/L, pH7.0) 28 ℃ of lucifuges were cultivated 10 days in, choose well-grown single strain and be inoculated in slant medium (soyflour 20g/L, N.F,USP MANNITOL 20g/L, agar 20g/L, pH7.0) cultivated 10 days for 28 ℃, take fresh spore inclined-plane in 40ml seed culture medium (starch 10g/L is housed, glucose 30g/L, peptone 6g/L, yeast powder 6g/L, lime carbonate 2g/L, initial pH7.0) 250ml shakes in the bottle, 28 ℃, cultivate 48h in the 200rpm shaking table, back 10% (v/v) is inoculated in 40ml fermention medium (starch 25g/L is housed, dextrin 45g/L, seitan powder 2.5g/L, peptone 6g/L, yeast powder 11g/L, corn steep liquor 6g/L, cold press soybean cake powder 6g/L, dipotassium hydrogen phosphate 1.5g/L, ammonium sulfate 1g/L, sal epsom 1.5g/L, lime carbonate 1.5g/L, initial pH7.0) 250ml shakes in the bottle, 28 ℃, cultivate 168h in the 180rpm shaking table, HPLC detects ascosin content, selects the inheritance stability mutant strain of high yield ascosin.Mutant strain positive mutation rate 8-10%.Fermentation unit improves 15-18% than original strain.
Claims (4)
1. a femtosecond laser mutagenesis streptomyces hygroscopicus ascus subspecies seed selection ascosin superior strain method is characterized in that comprising following process: with streptomyces hygroscopicus ascus subspecies at room temperature, get ripe spore inclined-plane and add an amount of sterilized water, make 10
6-10
7The monospore suspension of individual/ml, the suspension of 0.2ml is sub-packed in the centrifuge tube of aseptic 1.5ml, the titanium jewel femtosecond laser that adopts centre wavelength 800nm, pulsewidth 150fs, frequency 76MHz is under irradiation power 10-30mW, to this spore irradiation 1-10min, then spore suspension gradient dilution 10 through radiation treatment
3-10
4Doubly, getting spore liquid 0.1ml after the dilution coats in the solid plate substratum 28 ℃ and cultivates 10d, choose well-grown single strain and be inoculated in 28 ℃ of cultivations of slant medium 10d, connecing an amount of spore suspension shakes in the bottle in the 250ml that the 40ml seed culture medium is housed, cultivate 48h in 28 ℃, 200rpm shaking table, after be inoculated in the 250ml that the 40ml fermention medium is housed and shake in the bottle, cultivate 144-192h in 26 ℃-30 ℃, 180-220rpm shaking table, therefrom obtain the inheritance stability of mutagenesis, the mutant strain of streptomyces hygroscopicus ascus subspecies that fermentation unit improves.
2. the medium preparation in the method for claim 1 is characterized in that solid and slant medium are formed and content is: soyflour 15-25g/L, N.F,USP MANNITOL 15-25g/L, agar 18-22g/L, initial pH7.0.
3. the medium preparation in the method for claim 1, it is characterized in that liquid fermentation medium is formed and content is: starch 15-25g/L, dextrin 35-45g/L, seitan powder 2-3g/L, peptone 4-6g/L, yeast powder 8-12g/L, corn steep liquor 4-6g/L, cold press soybean cake powder 4-6g/L, dipotassium hydrogen phosphate 0.5-1.5g/L, ammonium sulfate 0.5-1.5g/L, sal epsom 0.5-1.5g/L, lime carbonate 0.5-1.5g/L, initial pH7.0.
4. the medium preparation in the method for claim 1 is characterized in that the liquid seeds liquid culture medium is formed and content is: starch 8-12g/L, glucose 25-35g/L, peptone 5-7g/L, yeast powder 5-7g/L, lime carbonate 1-3g/L, initial pH7.0.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104388492A (en) * | 2014-11-24 | 2015-03-04 | 苏州嘉禧萝生物科技有限公司 | Method for producing rapamycin by using streptomyces hygroscopicus |
| CN104762247A (en) * | 2015-03-23 | 2015-07-08 | 天津大学 | A genetic engineering strain for increasing the yield of ascomycin and a constructing method |
| CN107245460A (en) * | 2017-05-18 | 2017-10-13 | 福建省微生物研究所 | A kind of streptomyces hygroscopicus mutagenic strain of high yield ascosin and its application |
-
2011
- 2011-06-20 CN CN2011101656847A patent/CN102250872A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104388492A (en) * | 2014-11-24 | 2015-03-04 | 苏州嘉禧萝生物科技有限公司 | Method for producing rapamycin by using streptomyces hygroscopicus |
| CN104762247A (en) * | 2015-03-23 | 2015-07-08 | 天津大学 | A genetic engineering strain for increasing the yield of ascomycin and a constructing method |
| CN104762247B (en) * | 2015-03-23 | 2018-02-13 | 天津大学 | Improve the engineering strain and construction method of production ascosin yield |
| CN107245460A (en) * | 2017-05-18 | 2017-10-13 | 福建省微生物研究所 | A kind of streptomyces hygroscopicus mutagenic strain of high yield ascosin and its application |
| CN107245460B (en) * | 2017-05-18 | 2020-01-03 | 福建省微生物研究所 | Streptomyces hygroscopicus mutant strain for high yield of ascomycin and application thereof |
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