CN103374593A - Method for converting echinocandin B into echinocandin B parent nucleus through microbial fermentation - Google Patents
Method for converting echinocandin B into echinocandin B parent nucleus through microbial fermentation Download PDFInfo
- Publication number
- CN103374593A CN103374593A CN2012101103896A CN201210110389A CN103374593A CN 103374593 A CN103374593 A CN 103374593A CN 2012101103896 A CN2012101103896 A CN 2012101103896A CN 201210110389 A CN201210110389 A CN 201210110389A CN 103374593 A CN103374593 A CN 103374593A
- Authority
- CN
- China
- Prior art keywords
- ecb
- substrate
- parent nucleus
- fermentation
- conversion
- 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.)
- Granted
Links
Abstract
The invention discloses a method for converting echinocandin B into an echinocandin B parent nucleus through microbial fermentation. The method is characterized by comprising the following step of: adding an echinocandin B substrate in a fermentation process to carry out conversion, wherein the echinocandin B substrate is added in batches or added in a flowing manner.
Description
Technical field
The present invention relates to field of biological pharmacy, particularly, the present invention relates to by microbial fermentation ECB is converted into the method for ECB parent nucleus.
Background technology
Fungi infestation is its occurrence frequency or infecting kind is all constantly increasing, and particularly comprises that at immunosuppressed patient HIV the infected, organ transplantation person, tumour patient and those suffer from Other diseases and just carry out among the patient of immunotherapy.The main medicine that is used for the treatment of at present deep fungal infections is triazole antifungal agent thing and amphotericin B, although this two classes medicine plays an important role to the control deep fungal infections, but because these medicines because the appearance of poor selectivity, drug resistance fungal, to deficiencies such as the susceptibility of fungies such as aspergillus and Candida albicans are not strong, make the mortality ratio of deep fungal infection disease high.Therefore, seek a kind of new safely and effectively antifungal drug and just seem particularly important.
The fungal cell has cell walls and mammalian cell does not have cell walls, and therefore, fungal cell wall is the desirable target spot of novel antifungal drugs.The echinocandin class medicine that 20 century 70s are found is one group of natural product, structure is comprised of with different fatty acid side chains similar ring type polypeptide core, suppress β-(1 by the noncompetitive mechanism of action, 3)-D-dextran synthetic, cause the cell walls dextran emptying, osmotic transient fixed and fungal cell's dissolving and bring into play its antifungic action.Its mechanism of action is unique, and bad should rate low, but show has a broad antifungal spectrum, active strong characteristics as a kind of medicine of kill fungi, is the important selection medicine for the treatment of immunosuppressed patient and immune normal patient fungi infestation.The echinocandin class microbiotic mainly contains three types: B, C and D.Wherein ECB (Echinocandin B, ECB) is topmost type.ECB be to produce in being fermented by Eurotium Aspergilus nidulans and Aspergilus rugulosus of the people such as Nyfeler R. discovery in 1974, but because the existence of acyl side-chain makes it have certain hemolytic toxicity.Carry out structure of modification take ECB as lead compound, can obtain the compound that some have clinical value, such as Cilofungin (Cilofungin), Caspofungin (Caspofungin, MK991), MFG (Micafungin, FK463), anidulafungin (Anidulafungin, LY303366).Cilofungin is because toxicity and formulation problem have stopped research and development, but rear three is successively in U.S.'s (calendar year 2001), Japan (2002), the U.S. (2006) Initial Public Offering.
Wherein anidulafungin is to come company and the joint research and development exploitation of Vicuron Pharmaceuticals company by gift, and route of administration is intravenous drip.Animal experiment study shows, compares with MFG with Caspofungin, and anidulafungin is stronger to the aspergillus fumigatus activity, to the Candida albicans activity relatively a little less than.Its preparation process comprises following two steps: (1) is by microbial transformation---and the deacylation enzyme that the actinoplanes fermentation produces is to ECB (Echinocandin B; ECB) carry out catalysis; make the side chain fracture; generate ECB parent nucleus (Echinocandin B Nucleus, ECBN) and unsaturated fatty acids side chain.(2) adopt the method for chemosynthesis to add new side chain---penta oxygen-triphen carboxyl on the basis of parent nucleus.Wherein the preparation of parent nucleus is committed step.Present preparation for the ECB parent nucleus, the chemical process cost is higher, and microbial transformation has the following advantages: reaction conditions is gentle, product is single, chemo-selective, regioselectivity and the enantio-selectivity of height, be easy to purifying, free from environmental pollution and can finish some chemosynthesis and be difficult to the reaction carried out.
US Patent No. 7785826B2 describes the technique of ECB Transformed E CBN in detail.The main flow process of this technique comprises: after the ECB fermentation is finished, and centrifugal acquisition mycelium, the deacylase that then the mycelium Eddy diffusion is added purifying in water transforms.But the method operation is comparatively loaded down with trivial details.The molar yield of aforesaid method is 30%.
Therefore still need develop the method that new microbial fermentation is converted into ECB the ECB parent nucleus.
Summary of the invention
The invention provides a kind of method that simply ECB (ECB) is changed into ECB parent nucleus (ECBN), can carry out scale operation with fermentor tank.Main technique is produced ECB deacylase bacterial strain for fermentation, adds the ECB substrate that is dissolved in the solubility promoter in the fermenting process and transforms, and the substrate addition manner can be that portion-wise addition or stream add.
Therefore the invention provides the full cell fermentation of a kind of employing, the method for adding substrate in the fermenting process is converted into ECBN with ECB, and the method is implemented more simple and convenient.
Therefore the invention provides the method that a kind of microbial fermentation is converted into ECB the ECB parent nucleus, it is characterized in that described method comprises that adding during the fermentation the ECB substrate carries out resting cell, described substrate addition manner can add for portion-wise addition or stream.
As used in the present invention, term " stream adds " is exactly that substrate is dissolved in the solubility promoter, be made into desired concn, transform through continual the adding in the fermented liquid of feed supplement pipeline by the peristaltic pump motion, this mode can be controlled substrate interpolation speed and substrate addition by adjusting the peristaltic pump rotating speed.
The method specifically comprises following key step:
1) ECB deacylase bacterial strain is produced in fermentation;
2) the ECB substrate is dissolved in the solubility promoter, beginning is added the ECB substrate in the mode that portion-wise addition or stream add behind the fermentation 20-72h, transforms;
3) after conversion finishes, the fermented liquid suction filtration, the ECB parent nucleus is present in the filtrate.
Below describe each step of the inventive method in detail:
The step 1 of aforesaid method) in, the fermentation bacterial strain uses therefor can be natural zymogenic bacteria, for example actinoplanes utahensis; Also can be genetic engineering bacterium, for example streptomyces albus engineering strain.Can adopt condition well known to those skilled in the art to carry out the fermentation of ECB deacylase.
Because the water-soluble extreme difference of ECB, therefore it need to be dissolved in add in the fermentor tank in the solubility promoter transform step 2) in solubility promoter can be DMSO, methyl alcohol, ethanol, polysorbate60, ECB concentration is controlled at 80-120mg/ml in the solution.Because ECB concentration is lower, the solubility promoter that need to add when adding the ECB substrate is also just more, and too much solubility promoter can produce toxic action to cell, causes the thalline self-dissolving, and conversion capability descends.
Preferred embodiment begin to add substrate until thalline fermentation after 24-72 hour according to one of the present invention, if the portion-wise addition substrate, it is unsuitable too high to add first concentration of substrate, and concentration is controlled at 0.5-3.5mg/ml, preferred 1.0-3.0mg/ml.In the subsequent step, each substrate addition is controlled at 1.5-4.0mg/ml, preferred 2.0-3.0mg/ml, and substrate can divide 3-5 interpolation.If the mode of selecting stream to add is added substrate, the bottoms stream Acceleration Control is at 0.1-0.2mgml
-1H
-1, preferred 0.125mgml
-1H
-1In two kinds of substrate addition manners, final substrate addition is 6.0-10.0mg/ml.
According to of the present invention one preferred embodiment, if the portion-wise addition substrate, then in the fermentation conversion process with HPLC Quantitative Monitoring fermented liquid in the content of ECB parent nucleus, until 60～70% of last consignment of ECB substrate be converted finish after, add again the next batch substrate.
According to of the present invention another preferred embodiment, generate situation with HPLC monitoring ECB parent nucleus in the conversion process, after substrate has added, continue to transform for some time, after HPLC detects the ECB exhausted substrate, stop conversion.
The present invention is high, simple to operate with the molar yield that ECB is converted into the ECBN method, is fit to large-scale industrial production, has good commercial value.
Embodiment
In following examples, the HPLC detection method of ECBN is:
Moving phase: 0.2% ammonium acetate solution: acetonitrile=95: 5;
Post model: Féraud door LUNR C18 (2), 150 * 4.60mm, 3 μ m;
Column temperature: 40 ℃;
Flow velocity: 0.7ml/min;
Detect wavelength: 222nm.
Molar yield %=generates ECBN mole number/substrate ECB mole number * 100%
The HPLC detection method of ECB is:
Moving phase: water: acetonitrile=45: 55;
Post model: Féraud door LUNR C18 (2), 150 * 4.60mm, 3 μ m;
Column temperature: 40 ℃;
Flow velocity: 0.7ml/min;
Detect wavelength: 222nm.
Agents useful for same all can be from commercially available acquisition in following examples.Wherein substratum used yeast extract (Yeast extract) is available from U.S. Difco company; Tryptones (Trypton) is available from Britain Oxoid company, and oatmeal, yeast powder, peanut meal powder are available from Zhejiang Zhenyuan Pharmaceutical Co., Ltd, and all the other biochemical reagents are all available from Chemical Reagent Co., Ltd., Sinopharm Group.
The fermentation that embodiment 1 produces ECB deacylase bacterial strain
Bacterial classification: actinoplanes utahensis (Actinoplanes utahensis NRRL 12052)
Culture medium prescription:
Slant medium: yeast extract 0.3%, Fructus Hordei Germinatus extract 0.3%, Tryptones 0.5%, glucose 1.0%, agar 2.5%, pH 7.0-7.2 cultivated 5-7 days for 30 ℃;
Seed culture medium: sucrose 2.5%, oatmeal 2%, yeast powder 0.25%, K
2HPO
40.1%, KCl 0.05%, MgSO
47H
2O 0.05%, FeSO
47H
2O 0.0002%, and pH=6.8 cultivated 3-4 days for 30 ℃;
Fermention medium: sucrose 2.5%, peanut meal powder 1.2%, K
2HPO
40.1%, MgSO
47H
2O0.3%, pH=6.8,30 ℃ of fermentations.
Embodiment 2-5 is that portion-wise addition ECB substrate mode transforms in the fermenting process
Embodiment 2
1) ECB is dissolved in concentration is 100mg/ml in the pure methyl alcohol, behind the transformed bacteria fermentation 48h, adds ECB substrate 1.5mg/ml, begin to transform;
2) in the conversion process in the HPLC Quantitative Monitoring fermented liquid content of ECB parent nucleus add the time to determine the next batch substrate, wait 60～70% of adding ECB substrate be converted finish after, interpolation next batch substrate.
3) conversion was added ECB substrate 1.5mg/ml for the second time after 12 hours, continued to transform;
4) continue conversion after 16 hours, add for the third time ECB substrate 3.0mg/ml
5) continue conversion after 24 hours, the 4th interpolation ECB substrate 2.0mg/ml transforms;
6) continue conversion after 24 hours, the 5th interpolation ECB substrate 2.0mg/ml, HPLC monitoring conversion situation is treated the ECB exhausted substrate, conversion stops;
7) fermented liquid suction filtration, ECBN is present in the filtrate, and HPLC detection computations molar yield is 85%.
Embodiment 3
1) ECB is dissolved in concentration is 120mg/ml in the straight alcohol, behind the transformed bacteria fermentation 72h, adds ECB substrate 3.0mg/ml, begin to transform;
2) in the conversion process in the HPLC Quantitative Monitoring fermented liquid content of ECB parent nucleus add the time to determine the next batch substrate, wait 60～70% of adding ECB substrate be converted finish after, interpolation next batch substrate.
3) conversion was added ECB substrate 4.0mg/ml for the second time after 17 hours, continued to transform;
4) continue conversion after 24 hours, add for the third time ECB substrate 2.0mg/ml, HPLC monitoring conversion situation is treated the ECB exhausted substrate, and conversion stops;
7) fermented liquid suction filtration, ECBN is present in the filtrate, and HPLC detection computations molar yield is 90%.
Embodiment 4
1) ECB is dissolved in concentration is 80mg/ml in 30% the polysorbate60, behind the fermentation 24h, adds ECB substrate 0.5mg/ml, begin to transform;
2) in the conversion process in the HPLC Quantitative Monitoring fermented liquid content of ECB parent nucleus add the time to determine the next batch substrate, wait 60～70% of adding ECB substrate be converted finish after, interpolation next batch substrate.
3) conversion was added ECB substrate 1.5mg/ml for the second time after 8 hours, continued to transform;
4) continue conversion after 16 hours, add for the third time ECB substrate 2.0mg/ml
5) continue conversion after 24 hours, the 4th interpolation ECB substrate 2.0mg/ml, HPLC monitoring conversion situation is treated the ECB exhausted substrate, conversion stops;
6) fermented liquid suction filtration, ECBN is present in the filtrate, and HPLC detection computations molar yield is 92%.
Embodiment 5
1) ECB is dissolved in 15% the DMSO aqueous solution, concentration is 90mg/ml, behind the fermentation 48h, adds ECB substrate 3.5mg/ml, begins to transform;
2) in the conversion process in the HPLC Quantitative Monitoring fermented liquid content of ECB parent nucleus add the time to determine the next batch substrate, wait 60～70% of adding ECB substrate be converted finish after, interpolation next batch substrate.
3) conversion was added ECB substrate 2.5mg/ml for the second time after 24 hours, continued to transform;
4) continue conversion after 24 hours, add for the third time ECB substrate 2.0mg/ml, HPLC monitoring conversion situation is treated the ECB exhausted substrate, and conversion stops;
5) fermented liquid suction filtration, ECBN is present in the filtrate, and HPLC detection computations molar yield is 83%.
Embodiment 6-9 is that the mode that stream adds the ECB substrate in the fermenting process transforms
Embodiment 6
1) ECB is dissolved in concentration is 120mg/ml in the pure methyl alcohol, behind the transformed bacteria fermentation 72h, adds ECB substrate 2.5mg/ml, begin to transform;
2) conversion is after 8 hours, with 0.1mgml
-1H
-1Flow acceleration, add ECB substrate 60h.ECB parent nucleus generation content in the HPLC Quantitative Monitoring fermented liquid in the conversion process.
3) continuation transformed after current adding substrate was finished, and HPLC detects ECB substrate residual, treats the ECB exhausted substrate, and conversion stops;
4) fermented liquid suction filtration, ECBN is present in the filtrate, and HPLC detection computations molar yield is 83%.
Embodiment 7
1) ECB is dissolved in concentration is 110mg/ml in the straight alcohol, behind the transformed bacteria fermentation 48h, with 0.15mgml
-1H
-1Flow acceleration, add ECB substrate 72h.ECB parent nucleus generation content in the HPLC Quantitative Monitoring fermented liquid in the conversion process.
2) continuation transformed after current adding substrate was finished, and HPLC detects ECB substrate residual, treats the ECB exhausted substrate, and conversion stops;
3) fermented liquid suction filtration, ECBN is present in the filtrate, and HPLC detection computations molar yield is 80%.
Embodiment 8
1) ECB is dissolved in concentration is 80mg/ml in 15% the DMSO aqueous solution, behind the transformed bacteria fermentation 24h, adds ECB substrate 1.5mg/ml, begin to transform;
2) conversion is after 10 hours, with 0.125mgml
-1H
-1Flow acceleration, add ECB substrate 50h.ECB parent nucleus generation content in the HPLC Quantitative Monitoring fermented liquid in the conversion process.
3) continuation transformed after current adding substrate was finished, and HPLC detects ECB substrate residual, treats the ECB exhausted substrate, and conversion stops;
4) fermented liquid suction filtration, ECBN is present in the filtrate, and HPLC detection computations molar yield is 86%.
Embodiment 9
1) ECB is dissolved in concentration is 80mg/ml in 30% the polysorbate60, behind the transformed bacteria fermentation 48h, with 0.2mgml
-1H
-1Flow acceleration, add ECB substrate 40h.ECB parent nucleus generation content in the HPLC Quantitative Monitoring fermented liquid in the conversion process.
2) continuation transformed after current adding substrate was finished, and HPLC detects ECB substrate residual, treats the ECB exhausted substrate, and conversion stops;
3) fermented liquid suction filtration, ECBN is present in the filtrate, and HPLC detection computations molar yield is 82%.
Claims (10)
1. microbial fermentation is converted into the method for ECB parent nucleus with ECB, it is characterized in that described method comprises that adding during the fermentation the ECB substrate transforms, and the mode of adding the ECB substrate is that portion-wise addition or stream add.
2. method according to claim 1 is characterized in that said method comprising the steps of:
1) ECB deacylase bacterial strain is produced in fermentation;
2) the ECB substrate is dissolved in the solubility promoter, beginning is added the ECB substrate in the mode that portion-wise addition or stream add behind the fermentation 20-72h, transforms;
3) after conversion finishes, the fermented liquid suction filtration, the ECB parent nucleus is present in the filtrate.
3. method according to claim 2 is characterized in that step 2) described solubility promoter is selected from dimethyl sulfoxide (DMSO), methyl alcohol, ethanol or polysorbate60.
4. method according to claim 2 is characterized in that step 2) concentration of described ECB substrate in solubility promoter is 80-120mg/ml.
5. method according to claim 1 and 2, the mode that it is characterized in that adding the ECB substrate is portion-wise addition, the concentration of the ECB substrate that wherein adds for the first time is 0.5-3.5mg/ml, preferred 1.0-3.0mg/ml.
6. method according to claim 5, it is 3-5 time that substrate adds number of times, the concentration of each ECB substrate that adds is 1.5-4.0mg/ml, preferably 2.0-3.0mg/ml.
7. method according to claim 5 is characterized in that in the fermenting process content with ECB parent nucleus in the HPLC Quantitative Monitoring fermented liquid, until the 60-70% of last consignment of ECB substrate be converted finish after, add again the next batch substrate.
8. method according to claim 1 and 2, the mode that it is characterized in that adding the ECB substrate is that stream adds.
9. method according to claim 8 is characterized in that the bottoms stream acceleration is 0.1-0.2mgml
-1H
-1, preferred 0.125mgml
-1H
-1
10. method according to claim 1 and 2 is characterized in that generating situation with HPLC monitoring ECB parent nucleus in the conversion process, after substrate has added, continues to transform for some time, after HPLC detects the ECB exhausted substrate, stops to transform.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210110389.6A CN103374593B (en) | 2012-04-13 | 2012-04-13 | ECB is converted into the method for ECB parent nucleus by fermentable |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210110389.6A CN103374593B (en) | 2012-04-13 | 2012-04-13 | ECB is converted into the method for ECB parent nucleus by fermentable |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103374593A true CN103374593A (en) | 2013-10-30 |
| CN103374593B CN103374593B (en) | 2016-04-20 |
Family
ID=49460425
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210110389.6A Active CN103374593B (en) | 2012-04-13 | 2012-04-13 | ECB is converted into the method for ECB parent nucleus by fermentable |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103374593B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105648000A (en) * | 2014-11-19 | 2016-06-08 | 重庆乾泰生物医药有限公司 | A microbial enzymatic conversion method for echinocandin B |
| CN105669839A (en) * | 2014-12-05 | 2016-06-15 | 重庆乾泰生物医药有限公司 | Hydrate of echinocandin B mother nucleus or salt thereof, preparation method and application thereof |
| CN107779487A (en) * | 2016-08-27 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of method that ECB is converted using actinoplanes utahensis |
| WO2019076021A1 (en) * | 2018-04-25 | 2019-04-25 | 邦泰生物工程(深圳)有限公司 | Preparation method for hesperetin, preparation method for hesperetin intermediate, and biological enzyme used for preparing hesperetin |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080076149A1 (en) * | 2004-12-15 | 2008-03-27 | Sanofi-Aventis Deutschland Gmbh | Method for the deacylation of lipopeptides |
-
2012
- 2012-04-13 CN CN201210110389.6A patent/CN103374593B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080076149A1 (en) * | 2004-12-15 | 2008-03-27 | Sanofi-Aventis Deutschland Gmbh | Method for the deacylation of lipopeptides |
Non-Patent Citations (3)
| Title |
|---|
| AJ KREUZMAN,ET AL.: "Membrane-associated echinocandin B deacylase of Actinoplanes utahensis: purification, characterization,heterologous cloning and enzymatic deacylation reaction", 《JOURNAL OF INDUSTRIAL MICROBIOLOGY AND BIOTECHNOLOGY》, vol. 24, no. 3, 31 March 2000 (2000-03-31), pages 173 - 180 * |
| 丁彦博等: "新来源棘白霉素B脱酰基酶产生菌的筛选和转化条件优化", 《2011抗感染药物与耐药菌防控专题研讨会》, 31 October 2011 (2011-10-31), pages 173 - 179 * |
| 刘靓等: "棘白霉素类化合物脱酰基酶产生菌的转化工艺研究", 《化学与生物工程》, vol. 29, no. 2, 29 February 2012 (2012-02-29), pages 84 - 86 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105648000A (en) * | 2014-11-19 | 2016-06-08 | 重庆乾泰生物医药有限公司 | A microbial enzymatic conversion method for echinocandin B |
| CN105648000B (en) * | 2014-11-19 | 2019-08-13 | 重庆乾泰生物医药有限公司 | A kind of echinocandin B microbial enzyme method for transformation |
| CN105669839A (en) * | 2014-12-05 | 2016-06-15 | 重庆乾泰生物医药有限公司 | Hydrate of echinocandin B mother nucleus or salt thereof, preparation method and application thereof |
| CN105669839B (en) * | 2014-12-05 | 2019-08-13 | 重庆乾泰生物医药有限公司 | The hydrate and preparation method and purposes of a kind of echinocandin B parent nucleus or its salt |
| CN107779487A (en) * | 2016-08-27 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of method that ECB is converted using actinoplanes utahensis |
| WO2019076021A1 (en) * | 2018-04-25 | 2019-04-25 | 邦泰生物工程(深圳)有限公司 | Preparation method for hesperetin, preparation method for hesperetin intermediate, and biological enzyme used for preparing hesperetin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103374593B (en) | 2016-04-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5502033A (en) | Antimicrobial polypeptide compound a pharmaceutical composition comprising the same, and a method for treating infectious diseases | |
| CN103374593B (en) | ECB is converted into the method for ECB parent nucleus by fermentable | |
| CN103555591B (en) | Method and bacterial strain for fermentation preparation of Echinocandin B | |
| CN106279369A (en) | Antifungal and application thereof | |
| CN103074403B (en) | Method for converting echinocandin B by using microbial enzyme | |
| CN102443560A (en) | Gene engineering bacterium for high efficiency conversion of echinocandin B and preparation method thereof | |
| Hino et al. | Chemical diversity in lipopeptide antifungal antibiotics | |
| CN102226152B (en) | Cylindrocarpon didymium and method for preparing ginsenoside Rh2 by using same | |
| CN102517222A (en) | Strain used for converting dehydroepiandrosterone with high efficiency, and application thereof | |
| EP2671952B1 (en) | Method for preparing cyclic lipopeptide compound | |
| TW199162B (en) | ||
| CN108441529A (en) | A kind of fermentation process of micafen sodium precursor FR179642 | |
| CN101280333B (en) | Method for preparing penicillium antibacterial peptide from grey rose penicillium | |
| CN102443561B (en) | Gene engineering bacterium for efficiently converting Echinocandin B and preparation method thereof | |
| CN103509840B (en) | A kind of method improving anidulafungin precursor compound Echinocandin B output | |
| CN1294151C (en) | Marine fungi polysaccharide and its extraction method and use | |
| CN104817619A (en) | Antibacterial compound and application thereof | |
| CN105837590A (en) | Compound with anti-Candida albicans activity, preparation method and application thereof | |
| CN111187339B (en) | Method for extracting FR901379 from fermentation broth | |
| CN100460383C (en) | Compound and its preparation method and its application in pharmacy | |
| CN103897042A (en) | Glycosylated derivative of cyclic peptide compounds and preparation method and application thereof | |
| Kobayashi et al. | FR227244, a novel antifungal antibiotic from Myrothecium cinctum No. 002 II. Biological properties and mode of action | |
| CN106905342B (en) | The structure and its preparation of two kinds of active metabolites of rose yellow streptomycete | |
| CN100567299C (en) | New antifungal compound, Preparation method and use | |
| CN1245164A (en) | Echcin and its fermenting extraction process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |