CN103695509A - Method for producing Daptomycin by fed-batch decyl aldehyde fermentation - Google Patents
Method for producing Daptomycin by fed-batch decyl aldehyde fermentation Download PDFInfo
- Publication number
- CN103695509A CN103695509A CN201310644848.3A CN201310644848A CN103695509A CN 103695509 A CN103695509 A CN 103695509A CN 201310644848 A CN201310644848 A CN 201310644848A CN 103695509 A CN103695509 A CN 103695509A
- Authority
- CN
- China
- Prior art keywords
- fermentation
- daptomycin
- capraldehyde
- fed
- decyl aldehyde
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- KSMVZQYAVGTKIV-UHFFFAOYSA-N decanal Chemical compound CCCCCCCCCC=O KSMVZQYAVGTKIV-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 238000000855 fermentation Methods 0.000 title claims abstract description 34
- 230000004151 fermentation Effects 0.000 title claims abstract description 34
- 108010013198 Daptomycin Proteins 0.000 title claims abstract description 30
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 title claims abstract description 30
- 229960005484 daptomycin Drugs 0.000 title claims abstract description 30
- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 11
- 239000000243 solution Substances 0.000 claims description 11
- 239000006052 feed supplement Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 241000958215 Streptomyces filamentosus Species 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 238000013341 scale-up Methods 0.000 abstract 1
- 241000894006 Bacteria Species 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 229960003165 vancomycin Drugs 0.000 description 5
- 108010059993 Vancomycin Proteins 0.000 description 4
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 4
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- 108010028921 Lipopeptides Proteins 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000003570 biosynthesizing effect Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 229960004799 tryptophan Drugs 0.000 description 2
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical class NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 1
- 108010013639 Peptidoglycan Proteins 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000012262 fermentative production Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
The invention provides a method for producing Daptomycin by fed-batch decyl aldehyde fermentation. A decyl aldehyde solution is supplemented into a fermentation tank in a Streptomyces roseosporus fermentation culture process to produce the Daptomycin. Thus, the method provided by the invention can enhance the yield of the Daptomycin. The method provided by the invention widens the path for producing Daptomycin by a fermentation process; and the decyl aldehyde solution has low toxicity for cells and can exist in the form of liquid at normal temperature, and thus, can not crystallize due to low temperature, thereby ensuring the fed-batch effect. Besides, the method is suitable for laboratory small-tank fermentation of Daptomycin, and also suitable for scale-up production in industrialized big tanks.
Description
Technical field
The invention belongs to the production field of daptomycin, relate in particular to a kind of method that stream adds capraldehyde producing daptomycin by fermentation.
Background technology
Over nearly 10 years, the trend of Gram-positive drug-fast bacteria infection is in continuous rising.The difficult point for the treatment of clinically bacterium infection at present mainly concentrates on methicillin-resistant staphylococcus aureus (MRSA), the faecalis of vancomycin resistance (VRE), the golden Portugal bacterium (GISA) of glycopeptide class sensitivity etc., they are also the very high pathogenic agent of spreading rate profit lethality rate in Hospitals at Present, although the glycopeptide antibiotics such as vancomycin are treated this class infection and have been obtained certain curative effect, but in recent years, found clinically the resistant organism of vancomycin, and this trend is increasing gradually.Therefore the research of antimicrobial agent new antibiotic becomes again heat subject.Daptomycin all has good sterilization effect to above resistant organism, and preparation medication is convenient, and toxic side effect is little, becomes the best substitute of " pathogenic bacteria last line of defense---vancomycin "; What have more meaning is, daptomycin is as first product of cyclic lipopeptide microbiotic family, its chemical structure and mechanism of action are different from the microbiotic of existing all categories, be over nearly 40 years after mouthful oxazolidinones microbiotic, be applied to clinical unique new texture classification microbiotic, and daptomycin seldom causes generation resistance strain isolated in clinical trial.
Daptomycin (Daptomycin) is a kind of cyclic lipopeptide microbiotic obtaining from Streptomyces roseosporus (Streptomyces roseosporus) separation of fermentative broth, and its chemical structure is suc as formula shown in (I).From formula (I), can find out, daptomycin is comprised of 13 amino acid and 1 longer chain fatty acid, and wherein 10 amino acid form an amino acid ring, separately have 3 amino acid to be arranged in wire, and L-tryptophane (L-Trp) is endways upper, connects 1 n-capric acid.
Daptomycin not only has novel chemical structure, its binding mode is also different from the microbiotic of any existing listing: daptomycin can be upset cytolemma to amino acid whose transhipment, thereby hinder the biosynthesizing of bacteria cell wall peptidoglycan, change the character of cytoplasmic membrane; In addition, it can also be by destroying the cytolemma of bacterium, its content is leaked and reaches the object of sterilization.Daptomycin, by destroy bacterial cell membrane function from many aspects, can kill rapidly gram-positive microorganism, and make bacterium be difficult to its produce resistance (A.Raja et al., Nature Rev.Drug Discov., 2003,2,943-944).Daptomycin, except acting on most of clinical relevant gram-positive microorganisms, the more important thing is, it also presents powerful activity to the resistance isolated strains of X-1497, vancomycin and linwzolid etc. in testing in vitro.
The synthetic method of daptomycin has complete synthesis, the molecular design of chemistry and three kinds of techniques of biosynthesizing, and wherein the first two is planted due to complex technical process and the low commercial value that there is no of productive rate.At present, in industry, the ordinary method of production daptomycin is mainly to make by Streptomyces roseosporus strain fermentation.
Up to the present, also not yet about add the report of capraldehyde solution in feed supplement process.
Summary of the invention
For addressing the above problem, the present invention adopts following technical scheme:
Stream adds a method for capraldehyde producing daptomycin by fermentation, comprises fermentation culture, it is characterized in that: after fermentation culture 18h, add capraldehyde solution, until fermentation ends in every liter of fermented liquid with the flow velocity of 1.0～2.0ml/h toward feed supplement stream in fermentor tank.
Further, the mass concentration of described capraldehyde solution is 6.0%; The solvent of described capraldehyde solution is the mixed solution of second alcohol and water.
Beneficial effect of the present invention is as follows:
Widen the path of fermentative Production daptomycin, the one, capraldehyde solution is less to the toxicity of cell, and the 2nd, it can exist with the form of liquid at normal temperatures, can Yin Wendu not low and crystallization has ensured the effect that stream adds.In addition, the present invention is not only applicable to laboratory canister fermenting daptomycin, can on the large tank of industrialization, amplify production yet.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art further to understand the present invention, but not limit in any form the present invention.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make some distortion and improvement.These all belong to protection scope of the present invention.
embodiment 1
Stream adds a method for capraldehyde producing daptomycin by fermentation, comprises following content:
A. cultivate Streptomyces roseosporus seed liquor;
B. inoculation: the seed liquor obtaining in step a is inoculated in fermention medium;
C. fermentation culture: the postvaccinal substratum obtaining in step b is cultivated and fermented, and fermentation culture temperature is 30～32 ℃;
D. add capraldehyde solution: after fermentation culture 18h, to stream in fermented liquid, adding mass concentration is 6.0% capraldehyde solution (solvent is the mixed solution of second alcohol and water), the speed that stream adds is: in every liter of fermented liquid with the flow velocity of 1.0～2.0ml/h toward feed supplement in fermentor tank, until fermentation ends;
E. fermentation ends separation: after fermentation culture 48～168h, finish fermentation, the fermented liquid obtaining is extracted to separation, obtain described daptomycin.
embodiment 2
Stream adds a method for capraldehyde producing daptomycin by fermentation, comprises following content:
A. cultivate Streptomyces roseosporus seed liquor: the Streptomyces roseosporus bacterial strain of preservation is transferred on slant medium, cultivate 120h for 30 ℃, be then inoculated in liquid nutrient medium, in the shaking table of 30 ℃, cultivate 36h, obtain described Streptomyces roseosporus seed liquor.
B. inoculation: the seed liquor obtaining in step a is inoculated in fermention medium;
C. fermentation culture: the postvaccinal substratum obtaining in step b is cultivated and fermented, and fermentation culture temperature is 30～32 ℃;
D. add halfcystine: after fermentation culture 18h, to stream in fermented liquid, adding mass concentration is 6.0% capraldehyde solution (solvent is the mixed solution of second alcohol and water), the speed that stream adds is: in every liter of fermented liquid with the flow velocity of 1.0～2.0ml/h toward feed supplement in fermentor tank, until fermentation ends;
E. fermentation ends separation: after fermentation culture 48～120h, finish fermentation, the fermented liquid obtaining is extracted to separation, obtain described daptomycin.
Claims (2)
1. stream adds a method for capraldehyde producing daptomycin by fermentation, comprises fermentation culture, it is characterized in that: after fermentation culture 18h, add capraldehyde solution, until fermentation ends in every liter of fermented liquid with the flow velocity of 1.0～2.0ml/h toward feed supplement stream in fermentor tank.
2. according to the above-mentioned stream of claim 1, add the method for capraldehyde producing daptomycin by fermentation, it is characterized in that, the mass concentration of described capraldehyde solution is 6.0%; The solvent of described capraldehyde solution is the mixed solution of second alcohol and water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310644848.3A CN103695509A (en) | 2013-12-05 | 2013-12-05 | Method for producing Daptomycin by fed-batch decyl aldehyde fermentation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310644848.3A CN103695509A (en) | 2013-12-05 | 2013-12-05 | Method for producing Daptomycin by fed-batch decyl aldehyde fermentation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103695509A true CN103695509A (en) | 2014-04-02 |
Family
ID=50357172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310644848.3A Pending CN103695509A (en) | 2013-12-05 | 2013-12-05 | Method for producing Daptomycin by fed-batch decyl aldehyde fermentation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103695509A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100047873A1 (en) * | 2008-08-01 | 2010-02-25 | Antibioticos S.P.A | Process for the production of daptomycin |
| CN101928677A (en) * | 2009-06-26 | 2010-12-29 | 上海来益生物药物研究开发中心有限责任公司 | A strain producing lipopeptide compound A21978C and its application |
| CN102796680A (en) * | 2012-07-04 | 2012-11-28 | 鲁南新时代生物技术有限公司 | Streptomyces roseosporus and method for producing daptomycin by utilizing combined precursor |
-
2013
- 2013-12-05 CN CN201310644848.3A patent/CN103695509A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100047873A1 (en) * | 2008-08-01 | 2010-02-25 | Antibioticos S.P.A | Process for the production of daptomycin |
| CN101928677A (en) * | 2009-06-26 | 2010-12-29 | 上海来益生物药物研究开发中心有限责任公司 | A strain producing lipopeptide compound A21978C and its application |
| CN102796680A (en) * | 2012-07-04 | 2012-11-28 | 鲁南新时代生物技术有限公司 | Streptomyces roseosporus and method for producing daptomycin by utilizing combined precursor |
Non-Patent Citations (1)
| Title |
|---|
| 韩培等: "达托霉素生物合成研究进展及临床研究", 《中国医药工业杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101948769B (en) | Bacteria YXY-C1 for preparing gamma-polyglutamic acid by solid fermentation and products thereof | |
| US12129504B2 (en) | Caproate-producing bacterium with multiple substrate utilization capabilities and its applications | |
| CN1940078B (en) | A kind of preparation method of biological preservative phenyllactic acid | |
| CN101245362B (en) | Method for producing polypeptide antibiotic enramycin by fermentation method | |
| CN101884394B (en) | Composite microbial feed additive for chicken and preparation method thereof | |
| CN101326954A (en) | Ganoderma lucidum conversion wheat straw production method and application of ganoderma acid-containing feed | |
| CN101985605A (en) | Saprolegnia antagonist and application thereof | |
| CN105152355A (en) | Traditional Chinese medicine microbial fermented disease prevention water purifier for culture water and preparation method | |
| CN101333547A (en) | A method of controlling pH and fed-batch fermentation to produce phenyllactic acid | |
| RU2381270C1 (en) | STRAIN OF BACTERIA Clostridium acetobutylicum-PRODUCER OF BUTANOL, ACETONE AND ETHANOL | |
| CN101724571B (en) | Method for increasing yield of solid fermentation beauveria bassiana spores by adding nutrient substances | |
| CN103834585A (en) | Rhizospheric pseudomonad capable of largely producing phenazine-1-carboxylic acid and phenazine-1-amide | |
| CN104560766A (en) | Actinoplanes strain and application thereof | |
| CN103710291B (en) | The method of one strain bacillus megaterium Z2013513 and production phenyl-lactic acid thereof | |
| CN103695510A (en) | Method for producing Daptomycin by fed-batch methyl oleate fermentation | |
| CN102816717B (en) | Staphylococcus cohnii and method for preparing 5-aminolevulinic acid by using staphylococcus cohnii | |
| CN103695509A (en) | Method for producing Daptomycin by fed-batch decyl aldehyde fermentation | |
| CN102242073B (en) | Method for preparing daptomycin by fermentation | |
| CN104762328A (en) | Fermentation method of increasing anti-bacterial capability of fermentation liquid of marine bacillus subtilis | |
| CN103881922A (en) | Method for harvesting microalgae by using microorganism flocculant | |
| RU2560584C1 (en) | STRAIN OF BACTERIA Bacillus stratosphericus CAPABLE TO PRODUCE ETHANOL FROM LIGNOCELLULOSIC BIOMASS | |
| CN102191185B (en) | Biological control endophytic fungi - Aspergillus restrictus | |
| CN103222479B (en) | Use of Streptomyces sioyaensis metabolite in prevention and control of Colletotrichum lindemuthianum | |
| CN104611280A (en) | Method for rapidly and selectively breeding terramycin strains | |
| CN105385635A (en) | Preparation method for Bacillus megaterium powder |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140402 |
|
| RJ01 | Rejection of invention patent application after publication |