CN106434406A - Actinomycete producing borrelidin, and applications thereof - Google Patents

Actinomycete producing borrelidin, and applications thereof Download PDF

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CN106434406A
CN106434406A CN201610229401.3A CN201610229401A CN106434406A CN 106434406 A CN106434406 A CN 106434406A CN 201610229401 A CN201610229401 A CN 201610229401A CN 106434406 A CN106434406 A CN 106434406A
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borrelidin
actinomyces
methanol
zymotic fluid
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CN106434406B (en
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万传星
罗晓霞
周彪
胡文超
周忠波
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Tarim University
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    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
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Abstract

The present invention discloses a high-yield strain (the yield achieves 10-15 mg/L) producing borrelidin, wherein the strain is S.ghanaensis TRM78-24, is preserved in the China Center for Type Culture Collection on November 2, 2015, and has the preservation number of CCTCC NO:M201565. The invention further discloses a method for producing borrelidin by using the strain, and applications of the actinomycete and the produced borrelidin in prevention and control of cotton verticillium wilt.

Description

A kind of actinomyces producing borrelidin and application thereof
Technical field
The present invention relates to agricultural and field of medicaments, be specifically related to a kind of actinomyces that can produce borrelidin and newly originate Bacterial strain and utilize this bacterial strain to produce the method for borrelidin and the application in antagonism cotton verticillium wilt thereof.
Background technology
Borrelidin（Also known as Boli mycin, Borrelidin）It is the cyanogen two with cyclopentane-carboxylic acid and conjugation 18 membered macrolide compounds of alkene feature structure, the earliest by Berger et al. in 1949 from Lou Che Shi streptomycete （Streptomycete rochei）Isolated in metabolite.Borrelidin is except having extensive antibacterium, resisting very Beyond bacterium and Antimalarial, also there is good suppression new vessels and generate activity（IC50=0.8nM）, it is current antineoplastic One of focus compound of research and development.Patent（CN1732264A）Disclose the polyketide synthase producing borrelidin And application thereof；Patent（CN103442564B）Preventive and therapeutic effect to soybean phytophthora root rot.The invention discloses a strain and produce thin The superior strain of spiral voxel and the method utilizing this bacterial strain production borrelidin thereof, and utilize this bacterial strain and this compound Application in preventing and treating cotton verticillium wilt evil.
Content of the invention
The present invention provides a kind of actinomyces producing borrelidin, and cotton spoting verticillium wilt is had good by described actinomyces Prevention effect, is Ghana streptomycete（Streptomycesghanaensis）TRM78-24, on November 2nd, 2015 is in China's allusion quotation The center preservation of type culture collection（Preservation address is：Wuhan City, Hubei Province Wuhan University, postcode：430072）, preserving number is CCTCC NO：M2015656, after testing, result is survival.
Application in producing borrelidin for the described actinomyces.Described application, it is characterised in that include following step Suddenly：Cultivate described actinomyces under suitable conditions, it is thus achieved that zymotic fluid；Isolated and purified borrelidin from zymotic fluid.
Preferably, it cultivates described actinomycetic culture medium prescription and condition of culture is：Millet 10g/L, glucose 10g/L , peptone 3g/L, CaCO32g/L, NaCl 2.5 g/L, regulation pH is 7.2-7.4；It is inoculated in fermentation training by the inoculum concentration of 8% Support in base, 28 DEG C, shaking table is cultivated 7 days under the conditions of 180rpm.
Preferably, from zymotic fluid, the method for isolated and purified borrelidin is specially：After zymotic fluid filters, wet method loading To D101 or AB-8 macroporous resin chromatography；Then respectively with 50% ethanol solution, 95% ethanol solution wash-out；95% ethanol elution Liquid, reduced pressure concentration obtains the medicinal extract rich in borrelidin after removing solvent；Then by compression leg chromatographic isolation in ODS, successively By 50% methanol-water and 100% methanol-eluted fractions.100% methanol-eluted fractions position prepares borrelidin with 70% methanol-water then Sterling.
The invention still further relates to the application at preventing and treating cotton verticillium wilt for the described actinomyces.Preferably, it uses described unwrapping wire The zymotic fluid of bacterium, or separate its Active components further for preventing and treating cotton verticillium wilt.
The invention have the advantages that：Ghana streptomycete（S.ghanaensis）The main metabolites of TRM78-24 For borrelidin, the content that HPLC analyzes borrelidin in many batch fermentations liquid is 10-15mg/L, borrelidin and Producing strains Ghana streptomycete（S.ghanaensis）The zymotic fluid of TRM78-24 has good prevention effect to cotton spoting verticillium wilt.
Brief description
The electromicroscopic photograph of Fig. 1 Ghana streptomycete TRM78-24（Show fibrillae of spores and spore shape）；
The chemical constitution of Fig. 2 borrelidin；
Fig. 3 borrelidin1HNMR spectrogram；
Fig. 4 borrelidin13CNMR spectrogram；
The hsqc spectrum figure of Fig. 5 borrelidin；
The HMBC spectrogram of Fig. 6 borrelidin；
The NOESY spectrogram of Fig. 7 borrelidin；
Fig. 8 Ghana streptomycete（S.ghanaensis）The 16S rDNA sequence of TRM78-24.
Detailed description of the invention
It is further elucidated with the present invention below by the detailed description of detailed description of the invention, but be not the limit to the present invention System, only illustrates.
Embodiment one Ghana streptomycete（S.ghanaensis）The source of TRM78-24 be separately cultured
From the 0-30cm topsoil sample of cotton field, Alar Area, Xinjiang, use dilution spread flat band method, trained by Gause I Supporting base, 28 DEG C incubated, separates and obtains bacterial strain TRM78-24, and this bacterial strain fermentation liquor shows the antagonism to cotton spoting verticillium wilt bacterium Activity.
Embodiment two Ghana streptomycete（S.ghanaensis）The qualification of TRM78-24
(1) Ghana streptomycete（S.ghanaensis）The Microscopic Identification of TRM78-24
The electromicroscopic photograph of Ghana streptomycete TRM78-24 sees Fig. 1, and Electronic Speculum shows that its spore is ellipsoid shape, and fibrillae of spores helical form has Branch.
(2) Ghana streptomycete（S.ghanaensis）The molecular biology identification of TRM78-24
1 design of primers
Its sequence of actinomyces universal primer using is respectively：27F（5’-AGAGTTTGATCCTGGCTC-3’）And 1492R（5’- CGGCTACCTTGTTACGACTT-3’）, by AudioCodes biotechnology（Beijing）Co., Ltd synthesizes.
The extraction of 2 Biocontrol Strain TRM78-24 genomic DNAs
Collect in the sterile centrifugation tube that the TRM78-24 thalline on culture plate puts into 1.5 mL, add the 1 × TE of 480 μ L to buffer Liquid.Add 20 μ L lysozymes（50 mg·mL-1）, put in 37 DEG C of shaking tables, 200rpm shaken overnight.Often pipe adds 50 μ L 20% SDS, add 5 μ L 20 mg mL-1Proteinase K, put in 60 DEG C of shaking tables, 200 r/min vibration 1 h.Add 550 μ L's Phenol:Chloroform:Isoamyl alcohol（25:24:1）, 12000rpm centrifuges 10 min, takes supernatant and moves in another centrifuge tube, repeatedly extracts 2-3 Secondary.Take supernatant, add isopyknic absolute ethyl alcohol, add the sodium acetate of 0.1 times of volume（3mol·L-1）, put in 4 DEG C of refrigerators Precipitation DNA about 0.5h.12000rpm centrifuges 10min, abandons supernatant.Centrifuge product with 70% ethanol purge of 200 μ L 2 times, 12000rpm centrifuges 5 min, abandons supernatant, by ethanol volatilization completely.Fully dissolve the DNA of bottom with the 50 aseptic ultra-pure waters of μ L, 1% Agarose gel electrophoresis detection DNA extract quality, put into the DNA of extraction in-20 DEG C of refrigerators and save backup.
The amplification of 3 Biocontrol Strain TRM78-24 16S rDNA genes
With actinomyces 16S rDNA gene universal primer 27F（5’-AGAGTTTGATCCTGGCTC-3’）And 1492R（5’- CGGCTACCTTGTTACGACTT-3’）16S rDNA genetic fragment in amplification actinomyces genomic DNA.
The PCR reaction system of 25 μ L is：ddH2O 20.4 μ L, 10 × Buffer（Buffer solution contains Mg2+）2.5 μ L, dNTPs 0.5 μ L, primer 2 7F（10μmol·L-1）0.5 μ L, primer 1492R（10μmol·L-1）0.5 μ L, Taq archaeal dna polymerase 0.1 μ L, template DNA 0.5 μ L.
PCR reaction condition is：94 DEG C of 4 min of denaturation；94 DEG C of 1min of denaturation, anneal 56 DEG C of 1 min, extends 72 DEG C 2 min, 30 circulations；72 DEG C of 8min of overall elongation.Reaction is detected by 1% agarose gel electrophoresis after completing.Qualified PCR Product carries out sequencing.
4. the 16S rDNA sequencing results of biocontrol microorganisms TRM78-24
Sequencing result DNAMAN5.2 software splices, and determines that this fragment, by 1461 base compositions, obtains the 16S of TRM78-24 RDNA sequence refers to Fig. 8.
By GenBank database http://www.ezbiocloud.net/ BLAST comparison, biocontrol microorganisms TRM78-24 With Ghana streptomyceteStreptomyces ghanaensisThe 16S rDNA gene order of KCTC 9882 (T) is most like (uniformity is 99.93%), therefore this biocontrol microorganisms is accredited as Ghana streptomycete（S.ghanaensis）TRM78-24.
Embodiment three utilizes Ghana streptomycete（S.ghanaensis）TRM78-24 ferments and prepares borrelidin
Inoculation Ghana streptomycete（S.ghanaensis）The a small amount of conidia powder of TRM78-24, in ISP4 culture medium, cultivates 4d for 28 DEG C, Obtain seed liquor, take 2mL（The inoculum concentration of 8 %）Seed liquor is inoculated in fermented and cultured in millet fermentation medium, and fermentation condition is： Rotating speed 180 rpm, initial pH 7.2-7.4, liquid amount 250mL, fermentation temperature 28 DEG C, ferment 7d.Collect zymotic fluid, with four layers Filtered through gauze zymotic fluid, wet method is loaded to macroporous resin chromatography（The every 100L of ferment filtrate loads D101 or AB-8 macroreticular resin 2.0kg）；Then respectively with 50% ethanol-water solution, 95% ethanol-water solution wash-out；95% ethanol eluate, reduced pressure concentration goes Obtain 95% ethanol extract rich in borrelidin after falling solvent, then by compression leg chromatogram in ODS, respectively with 50% methyl alcohol- Water and 100% methanol-eluted fractions.100% methanol-eluted fractions position prepares borrelidin sterling, HPLC with 70% methanol-water then The content analyzing borrelidin in this zymotic fluid of display is 12.0mg/L, and actual preparation amount is 6.6mg/L.
The Structural Identification of embodiment four borrelidin
From Ghana streptomycete（S.ghanaensis）Compound isolated and purified in TRM78-24 zymotic fluid is pale powder；1H H NMR spectroscopy shows 3 alkene hydrogen signals（δ H6.28,6.57,6.87), 4 methyl signals（δ H0.83, 0.84, 0.85,1.02)（Refer to Fig. 3）,13C H NMR spectroscopy shows two carbonyls（δ C173.2,180.5), 4 olefinic carbon signals（δ C 140.2,129.0,145.4,119.9）, 3 company's oxygen carbon signals（δ C77.4, 73.1,72.9)（Refer to Fig. 4）.By than To document（The Journal of Antibiotics 42 (6): 1006-1007）And according to hsqc spectrum（Refer to Fig. 5）, It is borrelidin by this compound identification（borrelidin）（Fig. 2）, NMR signal belongs to table 1.The long-range dependency relation of HMBC It is further characterized by reliability of structure（Refer to Fig. 6,7）.
Table 1 borrelidin1H NMR and13C NMR spectral data
Table 11H NMR and13C NMR Data for borrelidin (600 and 200 MHz in MeOD)a
aAll assignments are based on HSQC and HMBC experiments.
The antibacterial activity to cotton spoting verticillium wilt for embodiment five borrelidin
Cultured cotton verticillium wilt disease fungus spore sterilized water is eluted from culture plate, makes 106-107Individual spore The spore suspension of son/mL, draws the spore suspension of 100 μ L to PDA plate, applies bacteria suspension with sterilized spreading rod Cloth is uniform, somewhat dries up on superclean bench.It is equidistantly placed Oxford cup on flat board carrying disease germs, each Oxford cup adds The borrelidin of 200 μ L variable concentrations gradients, with equivalent acetone for comparison, cultivates 6-7d for 28 DEG C, and right-angled intersection method measurement presses down Bacterium loop diameter, often processes and is repeated 3 times.Result shows, borrelidin suppression verticillium dahliae spore germination and mycelial growth EC50It is 60 μ g/mL.

Claims (8)

1. the actinomyces producing borrelidin, it is characterised in which is Ghana streptomycete（Streptomyces ghanaensis）TRM78-24, on November 2nd, 2015, its preserving number was CCTCC in China typical culture collection center preservation NO：M201565.
2. application in producing borrelidin for the actinomyces as claimed in claim 1.
3. apply as claimed in claim 2, it is characterised in that comprise the steps：Cultivate described actinomyces, it is thus achieved that fermentation Liquid；Isolated and purified borrelidin from zymotic fluid.
4. apply as claimed in claim 3, it is characterised in that cultivate described actinomycetic culture medium prescription and condition of culture For：Millet 10g/L, glucose 10g/L, peptone 3g/L, CaCO32g/L, NaCl 2.5 g/L, regulation pH is 7.2-7.4； It is inoculated in fermentation medium by the inoculum concentration of 8%, 28 DEG C, cultivate under the conditions of 180rpm.
5. apply as claimed in claim 4, it is characterised in that incubation time is 5-8 days.
6. the application as described in any one of claim 3 to 5, it is characterised in that：Isolated and purified borrelidin from zymotic fluid Method be specially：
After zymotic fluid filters, wet method is loaded to D101 or AB-8 macroporous resin chromatography；Then respectively with 50% ethanol solution, 95% Ethanol solution elutes；95% ethanol eluate, reduced pressure concentration obtains the medicinal extract rich in borrelidin after removing solvent；Then lead to Cross compression leg chromatographic isolation in ODS, successively by 50% methanol-water and 100% methanol-eluted fractions；100% methanol-eluted fractions position is then with 70% Methanol-water prepares borrelidin sterling.
7. actinomyces as claimed in claim 1 are in the application of preventing and treating cotton verticillium wilt.
8. apply as claimed in claim 7, it is characterised in that：It uses described actinomycetic zymotic fluid, or separates further Its Active components is used for preventing and treating cotton verticillium wilt.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1732264A (en) * 2002-12-27 2006-02-08 百奥帝卡技术有限公司 Borrelidin-producing polyketide synthase and its use
CN103409341A (en) * 2013-07-08 2013-11-27 浙江工业大学 Application of relA gene in increase of moenomycin yield of streptomyces bambergiensis and strain
CN103442564A (en) * 2011-03-25 2013-12-11 浙江海正药业股份有限公司 Effect of borrelidin for controlling soybean phytophthora root rot

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1732264A (en) * 2002-12-27 2006-02-08 百奥帝卡技术有限公司 Borrelidin-producing polyketide synthase and its use
CN103442564A (en) * 2011-03-25 2013-12-11 浙江海正药业股份有限公司 Effect of borrelidin for controlling soybean phytophthora root rot
CN103409341A (en) * 2013-07-08 2013-11-27 浙江工业大学 Application of relA gene in increase of moenomycin yield of streptomyces bambergiensis and strain

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
黄艳等: "一株加纳链霉菌种子培养工艺及移种标准的研究", 《中国畜牧杂志》 *

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