CN102586147A - Method for screening streptomyces roseosporus capable of producing Daptomycin at high yield - Google Patents
Method for screening streptomyces roseosporus capable of producing Daptomycin at high yield Download PDFInfo
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Abstract
The invention relates to a method for screening streptomyces roseosporus capable of producing Daptomycin at high yield, relating to a method for screening strains. In the method, the streptomyces roseosporus is used as an original strain, and glucose, malt extract, yeast extract, CaCO3 and agar powder are used as main raw materials of a culture medium, and the method is used for culturing strain spore and is applied to strain screening. The shake-flask fermentation biomass of the screened resistant strain is 30g/L, the yield of the Daptomycin is 59mg/L, and the yield is improved by 63.8% as compared with that of the original strain. Compared with the other screening methods, the method disclosed by the invention has the advantages of simpleness, convenience and high efficiency, can be used for screening a large amount of strains and can remarkably improve production capability of the Daptomycin of the streptomyces roseosporus; and in addition, the Daptomycin used as a new Lipopeptide antibiotic has excellent medical market prospect, and the method disclosed by the invention has remarkable economic and social significance.
Description
Technical field
The present invention relates to a kind of screening method of bacterial strain, but especially relate to a kind of screening method of Streptomyces roseosporus of high yield daptomycin.
Background technology
Daptomycin (Daptomycin) is the acid lipopeptide antibiotic of novel cyclic that is produced by Streptomyces roseosporus (Streptomyces roseosporus) fermentation, and this bacterial classification is obtained at the 1961's separation screening from Turkey's Ararat mountain soil sample by Falcao de Morias and Dailia Maia the earliest.
Daptomycin was just found and processes the vein injection subsequently to be used to treat gram positive bacteria infection by the researchist of Li Lai company as far back as the eighties in 20th century.Early stage in the eighties in 20th century and the nineties, carried out I phase and II phase and tested, wherein the participant is above 370.Test finds, daptomycin is encouraging to skin and soft tissue infection and bacteremic effect.The raising of dosage is also effective to infective endocarditis.
1997, Cubist company obtained the patent right of daptomycin from Li Lai company, and in bacteriemia and complex skin and soft tissue infection, had carried out I phase and II clinical trial phase respectively.In order to satisfy patient to the antibiotic active demand of novel resistance; The end of the year 2003; FDA (FDA) is used to treat the concurrency skin and the skin texture that are caused by some Gram-positive sensitive strains through quick trial program approval injection daptomycin (Daptomycin) (trade(brand)name cubicin) and infects, and infects and skin ulcer like abscess, operative incision.Through intravenous injection, the pharmacokinetics that daptomycin produces is linear, and the transformation period is 8h.In various animal models, daptomycin is to medicaments insensitive and the equal effective force of resistance gram-positive microorganism.The drug effect of ongoing phase III research severe infections that the research daptomycin causes gram-positive microorganism on the basis that is administered once every day comprises skin and soft tissue infection, group's acquired pneumonia and VRE infection.Its spinoff is little, and is safe.
Streptomyces roseosporus (Streptomyces roseosporus) has following characteristic: spore chain is straight type, do not curl, on each chain more than 10 spores, smooth redness and the light brown water colo(u)r of producing of spore surface; On agar-glucose plate culture medium, generate quality densification, velvet shape or fold, drying are arranged, the dry powder of opaque and white; The color of bacterium colony pros and cons is different and inconsistent because of substrate mycelium and spore institute chromogenesis, because of substrate mycelium combine with substratum tighter, so be difficult for provoking; And do not produce water colo(u)r.Because its spore color is redness or sorrel, physiological and biochemical test shows that its bacteriology characteristic is different with the known mode bacterial strain, is Streptomyces roseosporus (Streptomyces roseosporus) by class definition therefore.
Microbiotic produces the effect that bacterium has several aspects as metabolic end product to it: 1) carry out feedback regulation as end product to participating in the biosynthetic relevant enzyme of microbiotic; 2) to producing bacterium itself inhibition, killing effect are arranged.Therefore screening produces the raising of bacterium to the tolerance of self meta-bolites, will help the raising of microbiotic output.As: Du Run dissolves after primary streptomyces kanamyceticus (Streptomyces kanamyceticus) its spore suspension of gammairradiation with 1～100,000 roentgen; Bacterial strain reaches the bacterial strain of anti-2000～20000 μ g/mL high densitys by self meta-bolites of original tolerance 100～500 μ g/mL concentration, and fermentation unit improves 33.3% respectively than original strain.Wang Jin handles micronomicin through ultraviolet mutagenesis and produces bacterium, utilizes anti-self the metabolite characteristic seed selection of bacterial strain to obtain micronomicin and produces the mutant strain fermentation unit and improved 34.39% than starting strain.
In recent years; Though there is the relevant report of Streptomyces roseosporus seed selection work, and Lu Wenyu (Lu Wenyu. University Of Tianjin's journal, 2006; 39:20-14) reported that capric acid resistant mutant strain stream adds the correlative study of fermentative Production daptomycin; Zhou Jian (all swords. radiation research and radiation process journal, 2008,26 (5): 317-320) reported the research that utilizes the ion implantation Streptomyces roseosporus seed selection of nitrogen daptomycin superior strain.But utilizing associating resistance method to screen is always ignored by people.
Summary of the invention
But the object of the present invention is to provide a kind of screening method of Streptomyces roseosporus of high yield daptomycin.
Technical scheme of the present invention is to be starting strain with the Streptomyces roseosporus, with glucose, malt extract, yeast extract, CaCO
3, agar powder is used to cultivate the bacterial strain spore as the main raw material of substratum, is applied to bacterial strain screening work.
The bacterial classification that the present invention adopts is Streptomyces roseosporus D1000-S3-2 (Streptomyces roseosporus D1000-S3-2); Be preserved in Chinese typical culture collection center on July 5th, 2011; Address: Chinese Wuhan Wuhan University; Preservation center deposit number CCTCC NO:M2011236, this bacterial classification also can buy in American Type Culture Collecti (ATCC), strain number: Streptomyces roseosporus ATCC 11379.
The present invention includes following steps:
1) with sterilized water and the granulated glass sphere centrifuge tube of packing into, it is subsequent use to sterilize;
2) long good spore on the DA1 synthetic medium flat board is scraped into centrifuge tube;
3) centrifuge tube placed on the vibrator shake, spore is broken up and homodisperse, spore suspension;
4) preparation DA1 synthetic medium divides to be filled to triangular flask, and it is subsequent use to sterilize;
5) prepare daptomycin reference liquid and Streptomycin sulphate reference liquid respectively, subsequent use behind aseptic filtering with microporous membrane;
6) get the daptomycin reference liquid respectively and be added into the DA1 synthetic medium, rapid a kind of rhyme scheme in Chinese operas serving as the prelude to a complete score for voices processes 100,200,300,400,500,600, the daptomycin concentration gradient of 700mg/L is dull and stereotyped, be provided with do not add antibiotic dull and stereotyped as contrast;
7) get the Streptomycin sulphate reference liquid respectively and be added into the DA1 synthetic medium, rapid a kind of rhyme scheme in Chinese operas serving as the prelude to a complete score for voices processes 0.2,0.4,0.6,0.8,1.0,1.2, the Streptomycin sulphate concentration gradient of 1.4mg/L is dull and stereotyped, be provided with do not add antibiotic dull and stereotyped as contrast;
8) be coated on after the spore suspension that step 3) is made dilutes on daptomycin concentration gradient flat board and the Streptomycin sulphate concentration gradient flat board and cultivate;
9) observe the colony growth situation that the daptomycin concentration gradient is dull and stereotyped and the Streptomycin sulphate concentration gradient is dull and stereotyped, have the concentration of obvious minimizing to be the minimum inhibition concentration (MIC) of this microbiotic bacterial strain to compare bacterium colony with contrast;
10) resistant panel of 2～5 times of daptomycin MIC concentration of preparation;
11) resistant panel of 2～5 times of Streptomycin sulphate MIC concentration of preparation;
12) multiple resistance of 2～5 times of Streptomycin sulphate MIC concentration of preparation and 2～5 times of daptomycin MIC concentration is dull and stereotyped;
13) be coated on step 10)～12 with after the spore suspension dilution) on the multiple resistance flat board of resistant panel, the resistant panel of 2～5 times of Streptomycin sulphate MIC concentration, 2～5 times of Streptomycin sulphate MIC concentration and 2～5 times of daptomycin MIC concentration of 2～5 times of daptomycin MIC concentration of gained, be provided with do not add antibiotic dull and stereotyped as contrast;
14) flat board of coated spore is cultivated, the bacterium colony that grows is daptomycin and streptomycin resistant mutation strain;
15) muton that picking form and colour-change are bigger is transferred on the DA1 substratum behind the resistant panel purifying with isoconcentration and cultivates, and carries out the biological activity determination experiment, selects superior strain and carries out preservation.
In step 2) in, said scraping into centrifuge tube can adopt transfering loop to scrape into centrifuge tube.
In step 3), the time of said concussion can be 3～5min.
In step 4), the composition of said DA1 synthetic medium can be glucose 4.0g/L, malt extract 10g/L, yeast extract 4g/L, CaCO
32g/L, agar 15g/L.
In step 8), the multiple of said dilution can be 10～100 times; Said spore suspension can add 20% glycerine; Said culture condition can be cultivated 28～30 ℃ of culture temperature 7～9 days.
In step 14), said dull and stereotyped culture condition can be cultivated 7～9 days in 28～30 ℃ of incubators.
The resistant strain shake flask fermentation living weight that the present invention screens gained reaches 30g/L, and daptomycin output reaches 59mg/L, and original strain output improves 63.8% relatively.With respect to other screening methods, bacterial strain screening method of the present invention is easy, efficient, can be used for a large amount of screenings of bacterial strain, increases significantly for the daptomycin throughput of Streptomyces roseosporus.And a kind of new lipopeptide antibiotic of the conduct of daptomycin has good medical market outlook, and therefore the bacterial strain screening method of this invention has remarkable economical and social effect.
Description of drawings
Fig. 1 is the HPLC figure of daptomycin standard substance.In Fig. 1, X-coordinate is time/min; Peak 7.171 corresponding peak areas are 966.878.
Fig. 2 is the HPLC figure of fermentation broth sample.In Fig. 2, X-coordinate is time/min; Peak, a left side 7.202 corresponding peak areas are 1726.35, and right peak is 14.631.
Embodiment
Following examples will combine accompanying drawing that the present invention is further described.
Embodiment 1: the confirming of daptomycin minimum inhibitory concentration
Adopt solid medium DA1 to comprise glucose 4.0g/L, malt extract 10g/L, yeast extract 4g/L, CaCO
32g/L, agar 15g/L; Get daptomycin reference liquid filtrating respectively and be added into the DA1 synthetic medium in right amount, a kind of rhyme scheme in Chinese operas serving as the prelude to a complete score for voices rapidly processes 100,200,300,400,500,600, the daptomycin concentration gradient of 700mg/L is dull and stereotyped.Be provided with simultaneously and do not add antibiotic dull and stereotyped conduct contrast.Be coated on uniformly on the daptomycin concentration gradient flat board after 10～100 times of the spore suspension dilutions.Cultivated 7～9 days, 28～30 ℃ of culture temperature are observed each dull and stereotyped colony growth situation.The daptomycin of different concns to the influence of Streptomyces roseosporus growth referring to table 1.
The daptomycin of table 1 different concns is to the influence of Streptomyces roseosporus growth
Annotate: +++expression is looked; ++ expression looks general; + expression looks poor; The single colony counts of-expression is rare
Can know by table 1; Increase along with daptomycin concentration; The single bacterium colony of Streptomyces roseosporus on the screening flat board reduces gradually, and when daptomycin concentration reached 400mg/L, colonial morphology was very poor on the flat board; And the quantity of concentration single bacterium colony when reaching 500mg/L is very rare, is 400mg/L so can confirm Streptomyces roseosporus to the minimum inhibitory concentration (MIC) of daptomycin.
Embodiment 2: the confirming of Streptomycin sulphate minimum inhibitory concentration
Employing such as embodiment 1 said culture condition are investigated the influence of different concns Streptomycin sulphate to thalli growth.Its difference is that employed microbiotic is a Streptomycin sulphate.Get Streptomycin sulphate reference liquid filtrating and be added into the DA1 synthetic medium in right amount, a kind of rhyme scheme in Chinese operas serving as the prelude to a complete score for voices rapidly processes 0.2,0.4,0.6,0.8,1.0,1.2, the Streptomycin sulphate concentration gradient of 1.4mg/L is dull and stereotyped.Be provided with simultaneously and do not add antibiotic dull and stereotyped conduct contrast.Be coated on uniformly on the Streptomycin sulphate concentration gradient flat board after 10～100 times of the spore suspension dilutions.Cultivated 7～9 days, 28～30 ℃ of culture temperature are observed each dull and stereotyped colony growth situation.The Streptomycin sulphate of different concns to the influence of Streptomyces roseosporus growth referring to table 2.
The Streptomycin sulphate of table 2 different concns is to the influence of Streptomyces roseosporus growth
Annotate: +++expression is looked; ++ expression looks general; + expression looks poor; The single colony counts rareness of-expression can be known by table 2; Increase along with Streptomycin sulphate concentration; The single bacterium colony of Streptomyces roseosporus on the screening flat board reduces gradually, and when Streptomycin sulphate concentration reached 1.0mg/L, colonial morphology was very poor on the flat board; And the quantity of concentration single bacterium colony when reaching 1.2mg/L is very rare, is 1.0mg/L so can confirm Streptomyces roseosporus to the minimum inhibitory concentration (MIC) of daptomycin.
Embodiment 3: the resistance screening of many times of daptomycin MIC concentration
Employing such as embodiment 1 said culture condition; The daptomycin resistant panel concentration of preparation is 800,1000,1200,1400,1600mg/L; Wherein 1400 and the resistant panel of 1600mg L-1 on do not obtain mutant strain, and obtain 38 strain daptomycin resistant strains altogether 800,1000, on the 1200mgL-1 resistant panel.
Embodiment 4: the resistance screening of many times of Streptomycin sulphate MIC concentration
Employing such as embodiment 1 said culture condition; The dull and stereotyped concentration of the streptomycin resistance of preparation is 2.0,2.5,3.0,3.5,4.0,4.5,5.0mg/L; Wherein do not obtain mutant strain on the resistant panel of 5.0mg/L, and obtain 74 strain streptomycin resistance bacterial strains altogether 2.0,2.5,3.0,3.5,4.0, on the 4.5mg/L resistant panel.
Embodiment 5: daptomycin-Streptomycin sulphate multiple resistance screening
Employing such as embodiment 1 said culture condition, the daptomycin-Streptomycin sulphate multiple resistance of preparation different concns is dull and stereotyped like table 3, on resistant panel, obtains about 31 strains daptomycin-Streptomycin sulphate multiple resistance bacterial strain altogether.
The bacterial strain screening result that the daptomycin of table 3 different concns and Streptomycin sulphate multiple resistance are dull and stereotyped
Colonial morphology comparison through daptomycin-Streptomycin sulphate multiple resistance bacterial strain and original strain can get resistant strain and there is notable difference (result sees table 4) in the original strain colonial morphology.
Table 4 resistant strain and original strain colonial morphology diversity ratio are
Embodiment 6: utilize agar block method to carry out the checking of tentatively tiring of resistant strain
Employing such as embodiment 1 said culture condition, and in the DA1 substratum, add certain density precursor Sodium decanoic acid, concentration is 20～30mg/L.With original strain and mutant strain behind incubation growth to 7～9 under the identical condition day, with the punch tool punching of internal diameter 5mm. the agar together with following takes out, and measures the anti-microbial activity of mutant strain.
Dispose a certain amount of LB substratum, during sterilization postcooling to 50～60 ℃, add 0.1mL indicator (streptococcus aureus), pour petridish behind the mixing into.After solidifying, agar block to be measured is inverted on the substratum, places behind 4 ℃ of refrigerator 1h and cultivate, observe inhibition zone size (as illustrated in fig. 1 and 2) after 1～2 day in 37 ℃ of incubators with toothpick.Preliminary screening goes out resistant strain totally 15 strains of antibacterial circle diameter greater than original strain.Test-results is as shown in table 5.
Table 5 resistant strain agar block method primary dcreening operation result
Annotate: D representes daptomycin in the bacterial strain name, numeral daptomycin concentration thereafter,
S representes Streptomycin sulphate, thereafter numeral Streptomycin sulphate concentration.
Embodiment 7: the shake-flask culture of resistant strain and the checking of tiring
After above-mentioned 15 resistant strains that primary dcreening operation obtains inserted the shake-flask seed cultivation, the shake flask fermentation substratum was gone in switching, carried out shake flask fermentation and cultivated.The fermentation result measures daptomycin output with the HPLC method.Fig. 1 is the HPLC figure of daptomycin standard substance, and Fig. 2 is the HPLC figure of fermentation broth sample.The resistant strain daptomycin tire and dry cell weight referring to table 6.
Table 6 resistant strain daptomycin is tired and dry cell weight
The present invention screen Streptomyces roseosporus, the shake flask fermentation living weight reaches 30g/L, daptomycin output reaches 59mg/L, relatively original strain output improves 63.8%.
Claims (8)
1. but the screening method of the Streptomyces roseosporus of a high yield daptomycin; It is characterized in that said Streptomyces roseosporus D1000-S3-2 (Streptomyces roseosporus D1000-S3-2); Chinese typical culture collection center, preservation center deposit number CCTCC NO:M2011236 have been preserved in on July 5th, 2011;
Said screening method may further comprise the steps:
1) with sterilized water and the granulated glass sphere centrifuge tube of packing into, it is subsequent use to sterilize;
2) long good spore on the DA1 synthetic medium flat board is scraped into centrifuge tube;
3) centrifuge tube placed on the vibrator shake, spore is broken up and homodisperse, spore suspension;
4) preparation DA1 synthetic medium divides to be filled to triangular flask, and it is subsequent use to sterilize;
5) prepare daptomycin reference liquid and Streptomycin sulphate reference liquid respectively, subsequent use behind aseptic filtering with microporous membrane;
6) get the daptomycin reference liquid respectively and be added into the DA1 synthetic medium, rapid a kind of rhyme scheme in Chinese operas serving as the prelude to a complete score for voices processes 100,200,300,400,500,600, the daptomycin concentration gradient of 700mg/L is dull and stereotyped, be provided with do not add antibiotic dull and stereotyped as contrast;
7) get the Streptomycin sulphate reference liquid respectively and be added into the DA1 synthetic medium, rapid a kind of rhyme scheme in Chinese operas serving as the prelude to a complete score for voices processes 0.2,0.4,0.6,0.8,1.0,1.2, the Streptomycin sulphate concentration gradient of 1.4mg/L is dull and stereotyped, be provided with do not add antibiotic dull and stereotyped as contrast;
8) be coated on after the spore suspension that step 3) is made dilutes on daptomycin concentration gradient flat board and the Streptomycin sulphate concentration gradient flat board and cultivate;
9) observe the colony growth situation that the daptomycin concentration gradient is dull and stereotyped and the Streptomycin sulphate concentration gradient is dull and stereotyped, have the concentration of obvious minimizing to be the minimum inhibition concentration of this microbiotic bacterial strain to compare bacterium colony with contrast;
10) resistant panel of 2～5 times of daptomycin MIC concentration of preparation;
11) resistant panel of 2～5 times of Streptomycin sulphate MIC concentration of preparation;
12) multiple resistance of 2～5 times of Streptomycin sulphate MIC concentration of preparation and 2～5 times of daptomycin MIC concentration is dull and stereotyped;
13) be coated on step 10)～12 with after the spore suspension dilution) on the multiple resistance flat board of resistant panel, the resistant panel of 2～5 times of Streptomycin sulphate MIC concentration, 2～5 times of Streptomycin sulphate MIC concentration and 2～5 times of daptomycin MIC concentration of 2～5 times of daptomycin MIC concentration of gained, be provided with do not add antibiotic dull and stereotyped as contrast;
14) flat board of coated spore is cultivated, the bacterium colony that grows is daptomycin and streptomycin resistant mutation strain;
15) muton that picking form and colour-change are bigger is transferred on the DA1 substratum behind the resistant panel purifying with isoconcentration and cultivates, and carries out the biological activity determination experiment, selects superior strain and carries out preservation.
2. but the screening method of the Streptomyces roseosporus of a kind of high yield daptomycin as claimed in claim 1 is characterized in that in step 2) in, said scraping into centrifuge tube adopts transfering loop to scrape into centrifuge tube.
3. but the screening method of the Streptomyces roseosporus of a kind of high yield daptomycin as claimed in claim 1 is characterized in that in step 3), and the time of said concussion is 3～5min.
4. but the screening method of the Streptomyces roseosporus of a kind of high yield daptomycin as claimed in claim 1 is characterized in that in step 4), said DA1 synthetic medium consist of glucose 4.0g/L, malt extract 10g/L, yeast extract 4g/L, CaCO
32g/L, agar 15g/L.
5. but the screening method of the Streptomyces roseosporus of a kind of high yield daptomycin as claimed in claim 1 is characterized in that in step 8), and the multiple of said dilution is 10～100 times.
6. but the screening method of the Streptomyces roseosporus of a kind of high yield daptomycin as claimed in claim 1 is characterized in that in step 8) said spore suspension adds 20% glycerine.
7. but the screening method of the Streptomyces roseosporus of a kind of high yield daptomycin as claimed in claim 1 is characterized in that in step 8), and said culture condition is for cultivating 28～30 ℃ of culture temperature 7～9 days.
8. but the screening method of the Streptomyces roseosporus of a kind of high yield daptomycin as claimed in claim 1 is characterized in that in step 8), and in step 14), said dull and stereotyped culture condition was cultivated 7～9 days in 28～30 ℃ of incubators.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103937694A (en) * | 2013-01-22 | 2014-07-23 | 中国人民解放军军事医学科学院生物工程研究所 | High-expression daptomycin strains and screening method thereof |
| CN106133131A (en) * | 2013-12-18 | 2016-11-16 | 东国制药株式会社 | New thread streptomycete variant and use its method producing up to Tobramycin |
| CN113717909A (en) * | 2020-05-26 | 2021-11-30 | 杭州中美华东制药有限公司 | Daptomycin high-yield strain and application thereof |
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| CN101892287A (en) * | 2009-05-19 | 2010-11-24 | 上海医药工业研究院 | Screening method for breeding Streptomyces roseosporus strains producing Daptomycin and obtained strains |
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- 2012-02-17 CN CN2012100384233A patent/CN102586147A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101892287A (en) * | 2009-05-19 | 2010-11-24 | 上海医药工业研究院 | Screening method for breeding Streptomyces roseosporus strains producing Daptomycin and obtained strains |
Non-Patent Citations (3)
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| 张智翔等: "组合抗性筛选法选育达托霉素高产菌株", 《中国抗生素杂志》 * |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103937694A (en) * | 2013-01-22 | 2014-07-23 | 中国人民解放军军事医学科学院生物工程研究所 | High-expression daptomycin strains and screening method thereof |
| CN103937694B (en) * | 2013-01-22 | 2016-03-30 | 中国人民解放军军事医学科学院生物工程研究所 | The bacterial strain of high expression level daptomycin and screening method thereof |
| CN106133131A (en) * | 2013-12-18 | 2016-11-16 | 东国制药株式会社 | New thread streptomycete variant and use its method producing up to Tobramycin |
| CN106133131B (en) * | 2013-12-18 | 2020-01-03 | 东国制药株式会社 | Novel streptomyces filamentous variants and methods of producing daptomycin using same |
| CN113717909A (en) * | 2020-05-26 | 2021-11-30 | 杭州中美华东制药有限公司 | Daptomycin high-yield strain and application thereof |
| WO2021238832A1 (en) * | 2020-05-26 | 2021-12-02 | 杭州中美华东制药有限公司 | Daptomycin high-yield strain and application thereof |
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Application publication date: 20120718 |