CN1310766A - Improved process for clavulanic acid production - Google Patents
Improved process for clavulanic acid production Download PDFInfo
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- CN1310766A CN1310766A CN 99808891 CN99808891A CN1310766A CN 1310766 A CN1310766 A CN 1310766A CN 99808891 CN99808891 CN 99808891 CN 99808891 A CN99808891 A CN 99808891A CN 1310766 A CN1310766 A CN 1310766A
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- fermentation
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- 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
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
Abstract
The present invention concerns a process for clavulanic acid production by aerobic fermentation using selected and/or culture collection strains of Streptomyces clavuligerus, or mutants thereof. Accordingly, the culture is carried out with continuous or semicontinuous feeding of one or more organic nitrogen complex sources, preferably soybean meal, so as to control the protein concentration in the filtered broth within certain limits during the time course of the fermentation. The described conditions led to significant improvements in the clavulanic acid fermentation.
Description
Invention field
The present invention relates to use band spillikin streptomycete (Streptomyces clavuligerus) bacterial strain, low price complex medium and be easy to the important improvement of the strategy of industrial implementation the clavulanic acid fermentation.In the medicine clavulanic acid with can be used in combination by the microbiotic of beta-lactam enzyme-deactivating.
Background of invention
Clavulanic acid (3-(2-hydroxy ethylene)-7-oxo-4-Evil-1-azabicyclo [3.2.0] heptane-2-carboxylic acid) is a kind of molecule with following general structure:
This acid has weak anti-microbial activity.Yet it is a kind of potent inhibitor of the β-Nei Xiananmei of multiple bacterial strain generation such as streptococcus aureus (Staphylococcusaureus), intestinal bacteria (Escherichia coli), Klebsiella (Klebsiella), proteus (Proteus), Shigella (Shigella), Rhodopseudomonas (Pseudomonas) and Haemophilus influenzae (Haemophilus influenzae).β-Nei Xiananmei passes through several microbiotic of hydrolysis deactivation of beta-lactam nucleus, and makes the microorganism that produces them have resistance to these antibiosis.
As the potent inhibitor of β-Nei Xiananmei, clavulanic acid can be avoided this resistance mechanism, and several antibiotic anti-microbial activity spectrums of broadening.When combining with microbiotic such as amoxycillin, penbritin, Pyocianil, ticarcillin, penicillin G or Cephaloridine, clavulanic acid shows the anti-good synergistic activity that produces the β-Nei Xiananmei biology.
Several microorganisms clavulanic acids are arranged, promptly be with spillikin streptomycete, Streptomycesjumonjinensis (Spain's patent 543 854) and shore, osmanthus streptomycete (Streptomyceskatsurahamanus) (Japanese Patent 53-104796, Takeda Chemical Industries, Ltd.).For the clavulanic acid production of band spillikin streptomycete, several different methods has been described, for example (a) utilizes compound or chemical ingredients to determine the discontinuous fermentation (English Patent 1 508 977, Beecham Group Ltd.) of substratum; (b) control the fermentation that pH is 6.3-6.7 (English Patent 1 571 888, Glaxo Laboratories Ltd.) automatically; (c) the continuous or semicontinuous fermentation of adding carbon source (for example maltose or glycerine) (Spain's patent 537 157, Antibioticos, S.A.); (d) fermentation begin and whole process in control substratum in soluble phosphate fermentation (European patent 0 811 689, Antibioticos, S.A.).
In the discontinuous fermentation of band spillikin streptomycete of using the solubility substratum, it is closely related to observe time-histories and dry weight concentrations that clavulanic acid tires usually, till reaching maximum value, and both's reduction subsequently.The reduction of dry weight concentrations is attributable to sporulation and/or mycelium cracking.The reduction that clavulanic acid is tired may be because its degradation speed is higher than its generation speed.
Detailed Description Of The Invention
The present invention relates to a kind of clavulanic acid production method of utilizing fermentation technique, comprise the aerobic submerged culture of the selected plant that uses band spillikin streptomycete and/or preservation strain or its mutant.Therefore, in order during the fermentation the protein concn in the filtered culture liqs to be controlled within the certain limit, by continuous or semicontinuous add one or more compound organic nitrogen sources preferably soyflour cultivate.
Condition of the present invention successfully causes the following important improvement of clavulanic acid fermentation: (a) clavulanic acid output obviously improves; (b) prevent mycelium cracking in the fermenting process; (c) not tire increase continuously (not needing the partial discharge fermented liquid) with dry weight concentrations of clavulanic acid in the fermenting process; And/or (d) clavulanic acid is tired and is increased continuously, keeps substantially constant (partial discharge fermented liquid) from selecting the beginning dry weight concentrations sometime.
Therefore; the invention describes the new methods and strategies that clavulanic acid is produced; promptly with the distinct condition that has obtained patent protection or report so far under; in using complex medium at a low price aerobic submerged culture; cultivate and produce microorganism (as band spillikin streptomycete ATCC 27064 or its mutant), cause the important improvement of clavulanic acid fermentation.These conditions are continuously or one or more compound organic nitrogen sources are added in the compartment of terrain, during the fermentation the protein concn in the filtered culture liqs is controlled within the certain limit, because high concentration value can suppress/stop antibiotic biosynthesizing, and extremely low concentration value can limit the biosynthesizing of hope.Compound organic nitrogen source can be seed protein such as soyflour, peanut powder, cottonseed meal and linseed meal, fish meal, these proteinic hydrolysates and permeate, meat extract and hydrolysate such as peptone, preferably soyflour.The amount of the compound organic nitrogen source of adding in continuous or semicontinuous mode can be 0.1-1.5%, the day concentration of 0.18-1.0% preferably, and/or can be to make that the protein concn in the filtered culture liqs is 200-3500mg/L in the fermenting process, the amount of 400-1500mg/L preferably.
According to this method, initial medium can be made up of one or more compound organic nitrogen sources and one or more other carbon sources.The concentration of compound organic nitrogen source is 1.3-1.8% preferably.Carbon source can be glycerine and/or carbohydrate such as starch, starch hydrolysate, dextrin and maltose.Observing in initial medium preferably uses glycerine and dextrin can improve clavulanic acid output with the concentration of 0.9-1.3% and 1.8-2.2% respectively simultaneously.
In addition, also continuous or semicontinuous one or more carbon sources of adding with the day concentration of 0.18%-1% during the fermentation, and/or to make the glycerol concentration in the filtered culture liqs be 0.2-12g/L, and/or make dextrin or maltose concentration in the filtered culture liqs be respectively 4-22g/L or 2-12g/L.Observe and add glycerine and dextrin or maltose simultaneously and can improve clavulanic acid output.
Can ferment by continuous or semicontinuous partial discharge fermented liquid, make fermentating liquid volume remain the 35-65% of fermentor tank total volume like this.Can improve agitator speed gradually according to the increase of volume, nutrient solution viscosity and dry weight concentrations during the fermentation, with the level of mixing and dissolved oxygen in the raising culture.
Cultivation can be carried out under 26-29 ℃ of temperature, and can pH be controlled to be 6.5-6.8 by adding bronsted lowry acids and bases bronsted lowry (example hydrochloric acid solution and sodium hydroxide solution) automatically.Add defoamer such as siloxanes suspension may command foam.
Fermenting container should be the typical aerobic fermentation jar with stirring and breather.The ventilation volume flow velocity of per unit nutrient solution volume can be 0.6-1.3vvm.These jars should have and are used for the continuous or semicontinuous aseptic system of adding the nutrient of several solns and/or suspensions, have the aseptic system that is used for continuous or semicontinuous partial discharge fermented liquid, and may have variable agitator speed.
In order to carry out this analysis, preferably pass through 12 hours filter paper vacuum filtration nutrient solution sample of 86 ℃ of dryings in baking oven in advance.Behind the merging filtrate, contain mycelial filter paper, subsequently 86 ℃ of dryings 24 hours in baking oven with distilled water wash.Thereby obtain the dry weight concentrations of sample.
By spectrophotometry, or, for example use (Bird, people such as A.E., 1982, analyst (Analyst) 107:1241-1245 respectively preferably by the high pressure liquid chromatography (HPLC) method; Foulstone, M. and Reading, C., 1982, biocide chemotherapy (Antimicrob.AgentsChemother.) 22:753-762), (Bradford, M.M., 1976, analytical biochemistry (Anal.Biochem.) 72:248-254), (Bok, S.H. and Demain, A.L., 1977, analytical biochemistry 81:18-20), (Nelson, N., 1944, journal of biological chemistry (J.Biol.Chem.) 153:375-380; Somogyi, M., 1952, journal of biological chemistry 195:19-23) described method, can measure the concentration of clavulanic acid in the filtrate, protein, glycerine, dextrin or maltose.
The overview of having showed the result that obtains by following different embodiment.
Embodiment 1
Contain 10g hydration dextrin, 1g yeast extract, 1g meat extract, 2g microbial culture peptone, 2g CaCO from every liter of distilled water
3, 20g agar agar slant on the spore suspension of preparation band spillikin streptomycete ATCC 27064.With 1M NaOH and 1M HCl pH being proofreaied and correct is 7.1.
Contain 50mL culture medium A (every liter of distilled water 15g soyflour, 10g (87%) glycerine, 10g hydration dextrin, 1g KH with the inoculation of this spore suspension
2PO
4) different 500mL Erlenmeyer flasks.With 1M NaOH and 1M HCl pH being proofreaied and correct is 7.2.Flask is in 121 ℃ of sterilizations 15 minutes, and cultivates 2 days under 30 ℃ and 110-140 rev/min of condition.The content that mixes 5 flasks then obtains the nutrition inoculum.
In 8 liters of STR fermentor tanks, add 3.1L respectively and contain the substratum B that 15g soyflour, 13g (87%) glycerine, 20g hydration dextrin, 1g (50%) siloxanes suspension are formed, in about 120 ℃ of sterilizations 20 minutes down by every liter of tap water.Nutrition inoculum inoculation fermentation jar with previous preparation.
Automatically to control pH be 6.6 ± 0.05 by adding 5% (v/v) HCl solution and 1M NaOH solution, ferments.Add 50% siloxanes suspension control foam.Temperature remains 26-29 ℃, ventilates to be 0.7-1.2vvm.
In the time of 24 hours, begin to add at interval by every liter of tap water with the peristaltic pump of variable velocity and contain the culture medium C that 65g soyflour and 100g (87%) glycerine are formed.According to the day to protein in the filtered culture liqs and glycerol concentration analyzing the result, manual control volume flow velocity.Therefore, the following variation of volumetric flow rate in whole fermentation process:
The table I
Time (hour) | Flow velocity (mL/ hour) |
????24-79 ????79-101 ????101-159 ????159-166 | ????5 ????8 ????18 ????0 |
Because volume, nutrient solution viscosity and dry weight concentrations all increase in whole fermentation process, thus agitator speed manually improved, with the level of mixing and dissolved oxygen in the raising culture.Therefore, the following variation of agitator speed and dissolved oxygen concentration during the fermentation:
The table II
Time (hour) | Agitator speed (rev/min) | Dissolved oxygen (%) |
????0-24 ????24-56 ????56-72 ????72-79 ????79-96 ????96-101 ????101-117 ????117-166 | ????500 ????600 ????700 ????800 ????1000 ????1100 ????1200 ????1300 | ????100.0-75.6 ????89.6-52.5 ????56.8-48.5 ????51.3-49.9 ????48.5-29.7 ????41.7-34.3 ????36.9-39.2 ????45.9-21.6 |
Obtain in the whole fermentation process that dry weight concentrations, the clavulanic acid in fermentating liquid volume, the filtered culture liqs tired and the value of protein, glycerine and dextrin concentration is as follows:
The table III
Time (hour) | Volume (L) | Clavulanic acid (μ g/mL) | Dry weight (g/L) | Protein (mg/L) | Glycerine (g/L) | Dextrin (g/L) |
????0 ????24 ????48 ????72 ????96 ????120 ????144 ????166 | ????3.34 ????3.34 ????3.50 ????3.67 ????3.83 ????4.20 ????4.65 ????4.92 | ????0 ????90 ????441 ????698 ????857 ????1021 ????1096 ????1224 | ????5.3 ????7.0 ????9.6 ????11.2 ????12.2 ????13.8 ????14.7 ????15.6 | ????3064 ????860 ????511 ????494 ????674 ????854 ????911 ????1154 | ????10.9 ????9.0 ????8.6 ????7.0 ????3.9 ????4.4 ????4.5 ????2.8 | ?21.9 ?19.3 ?13.4 ?8.4 ?7.7 ?7.4 ?5.9 ?7.2 |
In whole fermentation process, all observe sporulation, and do not detect the mycelium cracking with microscope.
In the time of 166 hours, nutrient solution reaches the volume of 4.92L, and it is 1224 μ g/mL that clavulanic acid is tired, and dry weight concentrations is 15.6g/L.In other words, every milliliter of substratum B obtains 1943 μ g clavulanic acids and 24.8mg dry weight.
Embodiment 2
Except that following described change, as described in embodiment 1, ferment.
Add by every liter of tap water at interval since 24 hours fermentation times and to contain the substratum D that 65g soyflour, 56.3g (87%) glycerine, 86.6g hydration dextrin and 2g (50%) siloxanes suspension are formed, when fermentation ends till.According to the day to protein, glycerine and dextrin concentration in the filtered culture liqs analyzing the result, manual control volume flow velocity.Therefore, the following variation of volumetric flow rate in whole fermentation process:
The table IV
Time (hour) | Flow velocity (mL/ hour) |
????24-107 ????107-131 ????131-143 | ????11 ????19 ????11 |
Agitator speed and the following variation of dissolved oxygen concentration in whole fermentation times:
The table V
Time (hour) | Agitator speed (rev/min) | Dissolved oxygen (%) |
????0-24 ????24-55 ????55-75 ????75-107 ????107-131 ????131-143 | ????500 ????600 ????700 ????800 ????900 ????1000 | ????99.4-71.9 ????78.9-54.0 ????66.6-53.2 ????59.0-44.4 ????51.4-21.0 ????29.2-35.6 |
According to the increase of nutrient solution volume in the fermentor tank, in the time of 100 and 123 hours, carry out the partial discharge (8.3%v/v) of fermented liquid with the peristaltic pump of manually control.
Obtain in the fermenting process in fermentating liquid volume, fermented liquid partial discharge volume, the filtered culture liqs in heavy concentration, clavulanic acid is tired and the value of protein, glycerine and dextrin concentration is as follows:
The table VI
Time (hour) | Volume (L) | Partial discharge volume (L) | Clavulanic acid (μ g/mL) | Dry weight (g/L) | Protein (mg/L) | Glycerine (g/L) | Dextrin (g/L) |
????0 ????24 ????48 ????75 ????100 ????123 ????143 | ?3.24 ?3.26 ?3.56 ?3.88 ?4.20 ?4.21 ?4.75 | ?????- ?????- ?????- ?????- ????0.35 ????0.35 ??????- | ????0 ????91 ????426 ????801 ????1035 ????1264 ????1374 | ????5.5 ????6.8 ????10.6 ????14.2 ????16.2 ????17.3 ????18.7 | ????1673 ????718 ????634 ????318 ????464 ????674 ????647 | ?11.4 ?9.4 ?8.2 ?7.8 ?4.2 ?2.2 ?0.6 | ?20.8 ?18.3 ?19.0 ?16.1 ?17.5 ?24.6 ?22.8 |
(143 hours time) mycelium cracked begins when examining under a microscope sporulation in the whole fermentation process and fermentation ends.
In the time of 143 hours, nutrient solution reaches the volume of 4.15L, and it is 1374 μ g/mL that clavulanic acid is tired, and dry weight concentrations is 18.7g/L.In other words, every milliliter of substratum B obtains 1839 μ g clavulanic acids and 25.0mg dry weight.Consider partial discharge, every milliliter of substratum B obtains 2099 μ g clavulanic acids and 28.8mg dry weight altogether.
Embodiment 3
Except that following described change, ferment according to embodiment 1.
Substratum B replaced with by every liter of tap water contain the substratum E that 15g soyflour and 2g (50%) siloxanes suspension are formed.
Add by every liter of tap water at interval since 0 hour fermentation time and to contain the substratum F that 65g soyflour, 70g (87%) glycerine and 65g one hydration maltose are formed.According to the day to protein, glycerine and maltose concentration in the filtered culture liqs analyzing the result, manual control volume flow velocity.Therefore, in all following variations of fermentation time internal volume flow velocity:
The table VII
Time (hour) | Flow velocity (mL/ hour) |
????0-24 ????24-129 ????129-153 ????153-216 | ????5 ????11 ????22 ????11 |
The following variation of agitator speed and dissolved oxygen concentration in the fermenting process:
The table VIII
Time (hour) | Agitator speed (rev/min) | Dissolved oxygen (%) |
????0-24 ????24-48 ????48-72 ????72-146 ????146-216 | ????500 ????600 ????700 ????800 ????900 | ????98.6-68.9 ????74.4-79.9 ????82.0-73.1 ????80.6-51.7 ????54.4-37.9 |
According to the increase of nutrient solution volume in the fermentor tank, carry out the partial discharge of fermented liquid by the peristaltic pump of manual control.Carry out the partial discharge of 8.3%, 7.2%, 10.3%, 10.5% and 7.3% (v/v) fermented liquid during therefore, respectively at 96,120,144,168 and 192 hours.
Obtain in the fermenting process that dry weight concentrations, the clavulanic acid in fermentating liquid volume, fermented liquid partial discharge volume, the filtered culture liqs tired and the value of protein, glycerine and maltose concentration is as follows:
The table IX
Time (hour) | Volume (L) | Partial discharge volume (L) | Clavulanic acid (μ g/mL) | Dry weight (g/L) | Protein (mg/L) | Glycerine (g/L) | Maltose (g/L) |
????0 ????24 ????48 ????72 ????96 ????120 ????144 ????168 ????192 ????216 | ?3.14 ?3.32 ?3.62 ?3.93 ?4.20 ?4.16 ?4.35 ?4.28 ?4.10 ?4.02 | ?????- ?????- ?????- ?????- ????0.35 ????0.30 ????0.45 ????0.45 ????0.30 ?????- | ????0 ????123 ????496 ????759 ????904 ????1074 ????1164 ????1295 ????1475 ????1607 | ????5.4 ????7.0 ????10.2 ????11.9 ????13.2 ????13.9 ????15.7 ????16.1 ????16.3 ????16.6 | ????3137 ????962 ????742 ????625 ????770 ????862 ????850 ????853 ????810 ????936 | ????0.3 ????0.7 ????2.0 ????2.3 ????1.9 ????1.2 ????3.6 ????5.1 ????6.0 ????6.4 | ????2.5 ????2.7 ????3.8 ????4.6 ????5.3 ????4.7 ????7.8 ????8.2 ????7.9 ????8.2 |
In whole fermentation process, all observe sporulation, but do not detect the mycelium cracking with microscope.
In the time of 216 hours, nutrient solution reaches the volume of 4.02L, and it is 1607 μ g/mL that clavulanic acid is tired, and dry weight concentrations is 16.6g/L.In other words, every milliliter of substratum E obtains 2084 μ g clavulanic acids and 21.5mg dry weight.Consider partial discharge, every milliliter of substratum E obtains 2790 μ g clavulanic acids and 30.6mg dry weight altogether.
Claims (7)
1. utilize the clavulanic acid production method of fermentation technique, comprise the aerobic submerged culture of the selected plant that uses band spillikin streptomycete and/or preservation strain or its mutant, wherein, in order during the fermentation the protein concn in the filtered culture liqs to be controlled within the certain limit, by continuous or semicontinuous add one or more compound organic nitrogen sources preferably soyflour cultivate.
2. according to the process of claim 1 wherein that compound organic nitrogen source is a seed protein, as soyflour, peanut powder, cottonseed meal and linseed meal, fish meal, these proteinic hydrolysates and permeate, meat extract and hydrolysate such as peptone.
3. according to the method for claim 1 or 2, wherein the amount of the compound organic nitrogen source of adding in continuous or semicontinuous mode is 0.1-1.5%, the day concentration of 0.18-1.0% preferably, and/or make that the protein concn in the filtered culture liqs is 200-3500mg/L in the fermenting process, the amount of 400-1500mg/L preferably.
4. according to each method among the claim 1-3, wherein initial medium is that the compound organic nitrogen source of 1.3-1.8% and glycerine and dextrin that concentration is respectively 0.9-1.3% and 1.8-2.2% are formed by one or more concentration preferably.
5. according to each method among the claim 1-4, wherein in whole fermentation process with other continuous or semi-continuous glycerine and dextrin or the maltose added of day concentration of 0.18-1%, and/or to make the glycerol concentration in the filtered solution be 0.2-12g/L, and make dextrin or maltose concentration in the filtered solution be respectively 4-22g/L or 2-12g/L.
6. according to each method among the claim 1-5, wherein carry out the continuous or semicontinuous partial discharge of fermented liquid, so that fermentating liquid volume remains the 35-65% of fermentor tank total volume.
7. according to the method for aforementioned arbitrary claim, wherein improve agitator speed gradually according to the increase of volume, nutrient solution viscosity and dry weight concentrations during the fermentation, mix in the culture and the level of dissolved oxygen to improve.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PT10218198A PT102181A (en) | 1998-07-20 | 1998-07-20 | IMPROVED PROCESS FOR THE PRODUCTION OF CLAVULANIC ACID |
PT102181 | 1998-07-20 |
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Publication Number | Publication Date |
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CN1310766A true CN1310766A (en) | 2001-08-29 |
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CN 99808891 Pending CN1310766A (en) | 1998-07-20 | 1999-07-19 | Improved process for clavulanic acid production |
Country Status (8)
Country | Link |
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EP (1) | EP1098989A1 (en) |
CN (1) | CN1310766A (en) |
AU (1) | AU4808899A (en) |
CA (1) | CA2337074A1 (en) |
MX (1) | MXPA01000653A (en) |
PT (1) | PT102181A (en) |
TR (1) | TR200100167T2 (en) |
WO (1) | WO2000005397A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102933717A (en) * | 2007-04-27 | 2013-02-13 | 科学与工业研究委员会 | Process for preparation of clavulanic acid employing streptomyces clavuligerus mtcc 1142 in solid state fermentation |
Families Citing this family (2)
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CN102277310B (en) * | 2010-06-11 | 2013-04-10 | 中国科学院上海生命科学研究院 | Vector-host system for expressing antibiotic gene clusters and application thereof |
EP2589663A1 (en) | 2011-11-04 | 2013-05-08 | LEK Pharmaceuticals d.d. | Process for production of clavulanic acid |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE41110B1 (en) * | 1974-04-20 | 1979-10-24 | Beecham Group Ltd | Esters of clavulanic acid |
JPS51101994A (en) * | 1975-02-07 | 1976-09-08 | Glaxo Lab Ltd | |
ES2101658B1 (en) * | 1995-11-23 | 1998-03-01 | Antibioticos Sa | NEW PROCEDURE FOR THE PRODUCTION OF CLAVULANIC ACID AND ITS SALTS. |
-
1998
- 1998-07-20 PT PT10218198A patent/PT102181A/en not_active Application Discontinuation
-
1999
- 1999-07-19 TR TR2001/00167T patent/TR200100167T2/en unknown
- 1999-07-19 CN CN 99808891 patent/CN1310766A/en active Pending
- 1999-07-19 AU AU48088/99A patent/AU4808899A/en not_active Abandoned
- 1999-07-19 EP EP99931644A patent/EP1098989A1/en not_active Withdrawn
- 1999-07-19 CA CA002337074A patent/CA2337074A1/en not_active Abandoned
- 1999-07-19 MX MXPA01000653A patent/MXPA01000653A/en unknown
- 1999-07-19 WO PCT/PT1999/000012 patent/WO2000005397A1/en not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102933717A (en) * | 2007-04-27 | 2013-02-13 | 科学与工业研究委员会 | Process for preparation of clavulanic acid employing streptomyces clavuligerus mtcc 1142 in solid state fermentation |
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PT102181A (en) | 2000-01-31 |
AU4808899A (en) | 2000-02-14 |
MXPA01000653A (en) | 2002-04-08 |
EP1098989A1 (en) | 2001-05-16 |
CA2337074A1 (en) | 2000-02-03 |
TR200100167T2 (en) | 2001-05-21 |
WO2000005397A1 (en) | 2000-02-03 |
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