CN1332979C - New type antibiotic peptide of peptaibol and preparing technique - Google Patents
New type antibiotic peptide of peptaibol and preparing technique Download PDFInfo
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- CN1332979C CN1332979C CNB2004100758241A CN200410075824A CN1332979C CN 1332979 C CN1332979 C CN 1332979C CN B2004100758241 A CNB2004100758241 A CN B2004100758241A CN 200410075824 A CN200410075824 A CN 200410075824A CN 1332979 C CN1332979 C CN 1332979C
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Abstract
The present invention relates to pipomycin as novel antibiotic peptide and a preparation technology thereof, which belongs to the technical field of biology. Separation and purification pipomycin of the present invention is composed of 20 amino acids, an end N is acetyl and an end C is OH. Trichoderma strains which selects the high-yield antibiotic pipomycin ferments and producing trichoderma solid cultured matters by a liquid and solid combined fermentation technology in a GMP sterile environment. The pipomycin in high purified is prepared by an effective two-step separation technology. The three kinds of pipomycin has broad-spectrum antibacterial activity, has good inhibiting effects to various plant pathogenetic bacteria, disease fungus, viruses and plant root-knot nematode, and has preventive and therapeutic effects to various plant diseases.
Description
(1) technical field
The present invention relates to from the mould tunning of wood, separate a kind of new type antibiotic peptide-peptaibol of preparation, belong to biological technical field.
(2) background technology
Chemical pesticide has been made significant contribution to the human insect pests grass plague of rats, but along with using in a large number of chemical pesticide, " 3R " (is resistance Resistance, rampant again Resurgence, pesticide residue Residuce) problem is more and more serious, have a strong impact on the edible safety of agricultural-food, become agricultural products in China and enter one of main restricting factor of world market.It is an inevitable trend that the chemical pesticide of a large amount of high poison, high residue, killed natural enemies will be limited to use until total ban production gradually.According to Food and Argriculture OrganizationFAO (FAO) statistics, the world food output due to illness loss that causes of the Chinese caterpillar fungus plague of rats accounts for the 20-35% of gross output every year greatly, and wherein insect pest 14%, disease 10%; Cotton is because of insect pest loss 16%, and due to illness the evil loss 12%, and a year amount of loss reaches 1,200 hundred million dollars, is equivalent to 1/2 of the Chinese agriculture gross output value.Therefore, utilizing method control plant pest that microbial control combines with chemical prevention is effective means comparatively at present.Seek new disease and pest bio-control method, the various plant pests of high-efficiency prevention and control, the consumption of minimizing chemical pesticide, chemical pesticide is residual in the reduction agricultural-food, is the difficult problem in the production of being badly in need of at present solving.With respect to the successful Application of biotic pesticide in the insect pest of the plant control based on Bt, the difficulty of prevention and cure of various Plant diseasess (mycosis, bacteriosis, virus disease) is bigger, although use a large amount of chemical bactericides, but prevention effect is unsatisfactory, the crop disease-resistant breeding has obtained certain effect, but does not also tackle the problem at its root.
Control for people, animal poultry diease evil, particularly the bacteriosis of people, animal fowl prevent and treat the antibiotic use that is used for somatotrophic inferior therapeutic dose in antibiotic a large amount of uses in the process and the animal and fowl fodder, make The main pathogenic fungi strengthen greatly to antibiotic resistance.Pathogenetic bacteria has caused worldwide concern to antibiotic resistance, will have a strong impact on the treatment of bacteriosis.Therefore, the novel antibiotic medicine that exploitation is difficult for developing immunity to drugs, extremely urgent.
The mould biological and ecological methods to prevent plant disease, pests, and erosion factor as a kind of Plant diseases of wood is subjected to common attention always.The mould growth that is used for suppressing phytopathogen by habitat competition, antibiosis, generation cell wall degrading enzyme, induction of resistance, promotion plant-growth etc. of wood.The microbiotic of the mould generation of wood comprises trichodermin, gliotoxin, viridin and antibiotic peptide-peptaibol.Peptaibol is that a class is rich in α-An Jiyidingsuan (Aib), tool α-Luo Xuanjiegou by non-ribosomal synthetic enzyme (NRPSs) synthetic, bacterium, fungi etc. is had the general name of the special antibiotic peptide of a class of antagonistic action.Peptaibol is mainly derived from soil fungi, has had 309 kinds of peptaibols to be found at present, wherein derive from Trichoderma (Trichoderma spp) bacterial strain at most, reach 183 kinds.Peptaibol has the broad spectrum antimicrobial activity as the special antibiotic peptide of a class, and gram-positive microorganism and negative bacterium, fungi are all had good fungistatic effect.To spiral shell substance, the virus effect that also has certain effect.Except antimicrobial acivity, peptaibol has showed the various biological activity to zooblast, as the secretion that promotes catechol, promote hematoblastic polymerization, immunosuppressive action etc.Recently studies show that its metabolism to plant is also influential, be the potential inducible factor that plant secondary metabolism and tendril twine.As the special antibiotic peptide of a class of fungic origin, the understanding of people to antibiotic peptide has been enriched in the research of peptaibol.Its mechanism of action uniqueness is difficult for making pathogenic micro-organism to develop immunity to drugs, so the utmost point is hopeful to be developed to the new antibacterials of a class.But the peptaibol that is used to study at present nearly all is a synthetic, and synthetic cost is very high, and how a large amount of highly purified peptaibols of production becomes the difficult problem of restriction to its further investigation and application.
(3) summary of the invention
The present invention is directed to the mass-produced difficult problem of peptaibol of prior art, a kind of new type antibiotic peptide-peptaibol and preparation technology thereof are provided.
The peptaibol of separation and purification of the present invention is to be ethanoyl at 20 amino acid whose N ends, and the C end is OH, has following sequence:
Ac Aib Ala Aib Ala Aib Ala Gln Aib Val Aib Gly Leu Aib Pro Val Aib Aib Gln Gln Phe OH, Ac Aib Ala Aib Ala Aib Ala Gln Aib Val Aib Gly Leu Aib Pro Val Aib Iva Gln Gln Phe OH, or Ac Aib Ala Aib Ala Aib Aib Gln Aib Val Aib Gly Leu Aib Pro Val Aib Aib Gln Gln PheOH.
The preparation method of peptaibol of the present invention is as follows:
(1) trichoderma strain-healthy and free from worry wood mould (Trichoderma koningii SMF2) that adopts the high yield peptaibol is for producing bacterial strain, and inoculation triangular flask liquid spawn (second class inoculum) is a substratum with wheat bran juice, and liquid fermenting filling fermentative preparation is produced and used liquid spawn;
(2) be main raw material with corn stalk powder, Wheat Straw powder and wheat bran, be equipped with ammonium sulfate and water, sterilization, liquid spawn is used in the production of inoculation step (1) gained, changes aseptic solid fermentation Quchi over to, logical aseptic wind, the thick-layer ventilating fermentation prepares wooden mould fermenting culture;
(3) preparation of peptaibol with the wooden mould solid culture of step (2), obtains peptaibol through extraction, molecular sieving, HPLC purifying.
Each step to the preparation method of wooden removing mildew of the present invention specifies as follows below:
(1) produces the preparation of using liquid spawn
Substratum: 4～6 parts in 9～11 parts in wheat bran and potato, 100 parts in water is weight part, down together.Boil, filter, add 0.41～0.6 part of peptone, Na
2HPO
40.4～0.5 part, KH
2PO
40.03～0.04 part, sterilization are cooled off, and inoculate the second-class liquid isolate of healthy and free from worry wood mould (Trichoderma koningii SMF2), and 5～10 parts, ventilate and stir, cultivated 24～36 hours, stand-by as producing with liquid spawn.
(2) the thick-layer ventilating fermentation prepares wooden mould fermenting culture
Raw material: 30～40 parts in corn stalk powder and/or Wheat Straw powder, 60～70 parts in wheat bran, 1～2 part in ammonium sulfate, be weight part, profit water, raw material: water=1: 2.8～3.0 (weight ratio), the rotary spherical digester autoclave sterilization, cooling, 5～7 parts of liquid spawns (weight) are used in the production of inoculation step (1), change in the sterile solid fermentation Quchi, pass to aseptic wind, at 25～28 ℃, relative air humidity 80～85% bottom fermentations, turn over Qu Yici in 24～30 hours, fermented 4～5 days, promptly obtain wooden mould solid culture.
The mould solid culture of this wood, peptaibol content reaches 5～10mg/kg dry product.
(3) preparation of peptaibol
The amount of the mould solid culture of wood being pressed 8L～10L/kg dry weight adds about deionized water extraction 8～10hr, obtains the peptaibol crude extract, and through 10000rpm, 10min is centrifugal, and rotary evaporation is concentrated to 1/4～1/3 of original volume, obtains concentrated solution.Concentrated solution is crossed Sephadex G-15 molecular sieve column (5.0 * 150cm, medium Pharmacia), the component that is separated to is collected respectively with Fraction Collector, measure the each several part bacteriostatic activity, activated component is partly collected, further separate, according to retention time peptaibol is collected concentratedly then respectively, obtain 3 kinds of highly purified peptaibols with high pressure liquid chromatography.
(4) evaluation of peptaibol: the aminoacid sequence that obtains peptaibol by liquid matter logotype instrument and amino acid analysis is formed.
3 pure peptaibols that obtain are used the HCl all-hydrolytic of 6N, measuring amino acid with the amino acid automatic sequencer forms, analyze its molecular weight and the distribution of peptide section with liquid matter logotype instrument then, analyze the aminoacid sequence that draws three kinds of peptaibols and be respectively: Ac Aib Ala Aib Ala Aib Ala Gln Aib Val Aib Gly Leu Aib Pro Val Aib Aib Gln GlnPhe OH, Ac Aib Ala Aib Ala Aib Ala Gln Aib Val Aib Gly Leu Aib Pro Val Aib Iva Gln GlnPhe OH or Ac Aib Ala Aib Ala Aib Aib Gln Aib Val Aib Gly Leu Aib Pro Val Aib Aib Gln GlnPhe OH.
The bacteriostatic activity measuring method of above-mentioned steps (2), (3) adopts agar diffusion method, and indicator is the blue or green withered Lei Er Salmonella Ralstonia solanacearum Smith of Solanaceae.
The used high pressure liquid chromatography post of above-mentioned steps (3) is anti-phase C18 post.
Above-mentioned steps (4) amino acid analysis be with peptide with the HCl of 6N 115 ℃ of all-hydrolytics 22 hours, adopt the amino acid automatic sequencer to measure simultaneously.
Excellent results of the present invention is to select for use the trichoderma strain of high yield microbiotic peptaibol (peptaibols), utilizes liquid-solid two-phase combining with fermentation engineering, in the gnotobasis of GMP, and the mould solid culture of fermentative production wood.Adopt two step isolation technique efficiently then, obtain highly purified peptaibol.These three kinds of peptaibols have the bacteriostatic activity of wide spectrum, and various plants pathogenetic bacteria, pathogenic fungi, virus and plant root-knot nematode are had the good restraining effect, can have preventive and therapeutic effect to plurality of plant diseases.Peptaibol has the good restraining effect to multiple animal and human's pathogenetic bacteria (comprising Gram-positive and negative bacteria), and, such antibiotic mechanism of action is to form ionic channel on cytolemma, therefore, in the bacteriostatic process, be difficult for to form resistance, have great importance for the prevention and the treatment of present animal and human's the antibiotic strain of multiple height.
(4) description of drawings
Fig. 1 is a Sephadex G-15 molecular sieve column spectrogram in embodiment 1 step (3), flow velocity 0.6ml/min.
Fig. 2 is that embodiment 1 step (3) mesohigh liquid chromatography is separated spectrogram, flow velocity 1ml/min, and solvent systems: Meoh-water (82: 18 weight ratios), measure 214nm, detached peaks P1, P2 and P3 are 3 kinds of highly purified peptaibols.
Fig. 3 a-3b is 3 kinds of highly purified peptaibol bacteriostatic activity measurement result photos, and what inhibition zone occurs is the part that contains active ingredient.
(5) embodiment
Embodiment 1:
(1) produces the preparation of using liquid spawn
Substratum: 11 parts in wheat bran, 6 parts in potato, 100 parts in water is weight part, down together.Boil, filter, add 0.6 part of peptone, Na
2HPO
40.5 part, KH
2PO
40.04 part, sterilization, 10 parts of the second-class liquid isolates of healthy and free from worry wood mould (Trichodermakoningii SMF2) are inoculated in cooling, ventilate and stir, and cultivate 34 hours, use liquid spawn stand-by as producing.
(2) the thick-layer ventilating fermentation prepares wooden mould fermenting culture
Raw material: 35 parts in Wheat Straw powder, 70 parts in wheat bran, 2 parts in ammonium sulfate, be weight part, profit water, raw material: water=1: 3.0 (weight ratio), sterilization, cooling, 7 parts of liquid spawns (weight) are used in the production of inoculation step (1), change in the sterile solid fermentation Quchi, pass to aseptic wind, at 25～28 ℃, relative air humidity 80～85% bottom fermentations, turn over Qu Yici in 25 hours, fermented 4.5 days, promptly obtain wooden mould solid culture.
(3) preparation of peptaibol
The amount of the mould solid culture of wood by 8L～10L/10kg dry weight added about 95% extraction using alcohol 5hr, obtain the peptaibol crude extract, through 10000rpm, 10min is centrifugal, and rotary evaporation concentrates and obtains concentrated solution.Concentrated solution is crossed SephadexG-15 molecular sieve column (5.0 * 150cm, medium Pharmacia), the component that is separated to is collected respectively with Fraction Collector, measure the each several part bacteriostatic activity, activated component is partly collected, further separate, according to retention time peptaibol is collected concentratedly then respectively, obtain 3 kinds of highly purified peptaibols with anti-phase C18 post high pressure liquid chromatography.
(4) evaluation of peptaibol
With the HCl all-hydrolytic of the pure peptaibols of 3 of obtaining with 6N, measure amino acid with the amino acid automatic sequencer and form, analyze its molecular weight and the distribution of peptide section with liquid matter logotype instrument then, analyze the aminoacid sequence of three kinds of peptaibols.
Ac?Aib?Ala?Aib?Ala?Aib?Ala?Gln?Aib?Val?Aib?Gly?Leu?Aib?Pro?Val?Aib?Aib?Gln?Gln?Phe?OH、Ac?Aib?Ala?Aib?Ala?Aib?Ala?Gln?Aib?Val?Aib?Gly?Leu?Aib?Pro?Val?Aib?Iva?Gln?Gln?Phe?OH、AcAib?Ala?Aib?Ala?Aib?Aib?Gln?Aib?Val?Aib?Gly?Leu?Aib?Pro?Val?Aib?Aib?Gln?Gln?Phe?OH。
These three kinds of peptaibols have the bacteriostatic activity of wide spectrum, and various plants pathogenetic bacteria, pathogenic fungi, virus and plant root-knot nematode are had the good restraining effect, can have preventive and therapeutic effect to plurality of plant diseases.Bacteriostatic activity is measured and is adopted agar diffusion method, the Oxford cup: internal diameter 6 ± 0.1mm, and external diameter 7.8 ± 0.1mm, height 10 ± 0.1mm, indicator is the blue or green withered Lei Er Salmonella Ralstonia solanacearum Smith. of Solanaceae.Shown in Fig. 3 a-3b.What inhibition zone occurs is the part that contains active ingredient.
The outward appearance of the peptaibol of the embodiment of the invention is a white, is soluble in methyl alcohol.Characteristics of the present invention are to select for use the trichoderma strain of high yield microbiotic peptaibol (peptaibols), utilize liquid-solid two-phase combining with fermentation engineering, in the gnotobasis of GMP, and the mould solid culture of fermentative production wood.Adopt two step isolation technique efficiently then, obtain highly purified peptaibol, solved peptaibol efficient production problem, identified three kinds of peptaibols, for its theoretical investigation and Application and Development are laid a good foundation.These three kinds of peptaibols have the bacteriostatic activity of wide spectrum, and various plants pathogenetic bacteria, pathogenic fungi, virus and plant root-knot nematode are had the good restraining effect, can have preventive and therapeutic effect to plurality of plant diseases.Peptaibol has the good restraining effect to multiple animal and human's pathogenetic bacteria (comprising Gram-positive and negative bacteria), and, such antibiotic mechanism of action is to form ionic channel on cytolemma, therefore, in the bacteriostatic process, be difficult for to form resistance, have great importance for the prevention and the treatment of present animal and human's the antibiotic strain of multiple height.
Sequence table
＜110〉Shandong University
＜120〉new type antibiotic peptide of peptaibol and preparation technology thereof
<140>
<141>
<160>1
<170>Patent?In3.1
<210>1
<211>20
<212>PRT
<400>1
Ac?Aib?Ala?Aib?Ala?Aib?Ala?Gln?Aib?Val?Aib?Gly?Leu?Aib?Pro?Val?Aib?Aib?Gln?Gln?Phe?OH
1 5 10 15 20
<210>2
<211>20
<212>PRT
<400>2
Ac?Aib?Ala?Aib?Ala?Aib?Ala?Gln?Aib?Val?Aib?Gly?Leu?Aib?Pro?Val?Aib?Iva?Gln?Gln?Phe?OH
1 5 10 15 20
<210>3
<211>20
<212>PRT
<400>3
Ac?Aib?Ala?Aib?Ala?Aib?Aib?Gln?Aib?Val?Aib?Gly?Leu?Aib?Pro?Val?Aib?Aib?Gln?Gln?Phe?OH
1 5 10 15 20
Claims (6)
1, the peptaibol of separation and purification is characterized in that at 20 amino acid whose N ends are ethanoyl, and the C end is OH, has following sequence:
Ac Aib Ala Aib Ala Aib Ala Gln Aib Val Aib Gly Leu Aib Pro Val Aib Aib Gln Gln Phe OH, Ac Aib Ala Aib Ala Aib Ala Gln Aib Val Aib Gly Leu Aib Pro Val Aib Iva Gln Gln Phe OH, or Ac Aib Ala Aib Ala Aib Aib Gln Aib Val Aib Gly Leu Aib Pro Val Aib Aib Gln Gln PheOH.
2, the preparation method of the described peptaibol of claim 1, step is as follows:
(1) adopting healthy and free from worry wood mould is to produce bacterial strain, and inoculation triangular flask liquid spawn is a substratum with wheat bran juice, and liquid fermenting filling fermentative preparation is produced and used liquid spawn;
(2) be main raw material with corn stalk powder, Wheat Straw powder and wheat bran, be equipped with ammonium sulfate and water, sterilization, liquid spawn is used in the production of inoculation step (1) gained, changes aseptic solid fermentation Quchi over to, logical aseptic wind, the thick-layer ventilating fermentation prepares wooden mould fermenting culture;
(3) with the wooden mould solid culture of step (2), obtain peptaibol through extraction, molecular sieving, high pressure liquid chromatography purifying.
3, as the preparation method of peptaibol as described in the claim 2, it is characterized in that described production is specially with the preparation of liquid spawn: 4～6 parts in 9～11 parts in substratum wheat bran and potato, 100 parts in water boils, and filters, and adds 0.41～0.6 part of peptone, Na
2HPO
40.4～0.5 part and KH
2PO
40.03～0.04 part, sterilization, the mould second-class liquid isolate of healthy and free from worry wood is inoculated in cooling, and 5～10 parts, ventilate and stir, cultivated 24～36 hours, be weight part.
4, preparation method as peptaibol as described in the claim 2, it is characterized in that, described thick-layer ventilating fermentation prepares wooden mould fermenting culture and is specially: 30～40 parts in raw material corn stalk powder and/or Wheat Straw powder, 60～70 parts in wheat bran, 1～2 part in ammonium sulfate, profit water, raw material: water=1: 2.8～3.0 weight ratios, sterilization, cooling, the production of inoculation step (1) changes in the sterile solid fermentation Quchi with 5～7 parts of liquid spawns, pass to aseptic wind, at 25～28 ℃, relative air humidity 80～85% bottom fermentations turned over Qu Yici in 24～30 hours, fermented 4～5 days, and be weight part.
5, as the preparation method of peptaibol as described in the claim 2, it is characterized in that, described step (3) is with the amount adding deionized water extraction 8～10hr of the mould solid culture of wood by 8L～10L/kg dry weight, obtain the peptaibol crude extract, through 10000rpm, 10min is centrifugal, and rotary evaporation is concentrated to 1/4～1/3 of original volume, obtains concentrated solution; Concentrated solution is crossed Sephadex G-15 molecular sieve column, the component that is separated to is collected respectively with Fraction Collector, measure the each several part bacteriostatic activity, activated component is partly collected, further separate with high pressure liquid chromatography, according to retention time peptaibol is collected concentratedly then respectively, obtained 3 kinds of highly purified peptaibols.
As the preparation method of peptaibol as described in the claim 5, it is characterized in that 6, described mensuration bacteriostatic activity adopts agar diffusion method, indicator is the blue or green withered Lei Er Salmonella of Solanaceae.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100758241A CN1332979C (en) | 2004-12-27 | 2004-12-27 | New type antibiotic peptide of peptaibol and preparing technique |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100758241A CN1332979C (en) | 2004-12-27 | 2004-12-27 | New type antibiotic peptide of peptaibol and preparing technique |
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|---|---|
| CN1660894A CN1660894A (en) | 2005-08-31 |
| CN1332979C true CN1332979C (en) | 2007-08-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100758241A Expired - Fee Related CN1332979C (en) | 2004-12-27 | 2004-12-27 | New type antibiotic peptide of peptaibol and preparing technique |
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| US20150167040A1 (en) * | 2012-08-06 | 2015-06-18 | Danisco Us Inc. | Fungal Cells That Produce Decreased Amounts of Peptaibols |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999012958A2 (en) * | 1997-09-11 | 1999-03-18 | Hans-Knöll-Institut für Naturstoff-Forschung e.V. | Ampullosporin, method for producing same and its use |
| WO2000068256A1 (en) * | 1999-05-05 | 2000-11-16 | Aventis Pharma Deutschland Gmbh | Cephaibols, novel antiparasitics from acremonium tubakii, method for the production and the utilization thereof |
| DE19948644A1 (en) * | 1999-10-01 | 2001-04-05 | Knoell Hans Forschung Ev | New peptaibol peptides produced by Sepedonium fungus, useful as antibacterial, antifungal, neuroleptic and anxiolytic agents |
| DE10238697A1 (en) * | 2002-08-23 | 2004-03-11 | Hans-Knöll-Institut für Naturstoff-Forschung e.V. | New peptaibol peptide compounds having high alpha-aminoisobutyric acid content, useful for treating neurological diseases such as schizophrenia, obtained by culturing Trichoderma strain |
-
2004
- 2004-12-27 CN CNB2004100758241A patent/CN1332979C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999012958A2 (en) * | 1997-09-11 | 1999-03-18 | Hans-Knöll-Institut für Naturstoff-Forschung e.V. | Ampullosporin, method for producing same and its use |
| WO2000068256A1 (en) * | 1999-05-05 | 2000-11-16 | Aventis Pharma Deutschland Gmbh | Cephaibols, novel antiparasitics from acremonium tubakii, method for the production and the utilization thereof |
| DE19948644A1 (en) * | 1999-10-01 | 2001-04-05 | Knoell Hans Forschung Ev | New peptaibol peptides produced by Sepedonium fungus, useful as antibacterial, antifungal, neuroleptic and anxiolytic agents |
| DE10238697A1 (en) * | 2002-08-23 | 2004-03-11 | Hans-Knöll-Institut für Naturstoff-Forschung e.V. | New peptaibol peptide compounds having high alpha-aminoisobutyric acid content, useful for treating neurological diseases such as schizophrenia, obtained by culturing Trichoderma strain |
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