CN105154490A - Dectomax fermentation production method with OUR as control parameter - Google Patents
Dectomax fermentation production method with OUR as control parameter Download PDFInfo
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- 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
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Abstract
The invention discloses a dectomax fermentation production method with the OUR as a control parameter. The optimal dectomax fermentation control technology key parameter obtained through real-time online analysis of tail gas through a gas mass spectrometer and online calculation of a software package in the dectomax fermentation process is characterized in that a two-stage OUR control strategy is adopted, the optimal OUR of thalli is adjusted and controlled through the stirring rotating speed and ventilation oxygen supplying in first 0-50 hours of the dectomax fermentation process to range from 28-30 mmol/l/h, wherein due to the high OUR, hyphae rapidly grow, and valence is rapidly generated; in the next 50-260 h of the differentiation fermentation stage, the optimal OUR is controlled through the stirring rotating speed, ventilation oxygen supplying and continuous ammonium sulfate adding to be at the level of 18-21 mmol/l/h, and the reasonable OUR level is controlled in the later period. Glucose consumption and aging of hyphae are reduced, synthesized dectomax is promoted to be rapidly increased, the high synthesis speed is maintained for a long time, and the fermentation yield of the dectomax in 260 hours can be as high as 1,934 ug/ml.
Description
Technical field
The present invention relates to doractin production field, being specifically related to is the doractin fermentation method for producing of controling parameters based on oxygen consumption rate OUR.
Background technology
Doractin, commodity " lead to and go out " (Dectomax) by name, be the Macrolide broad-spectrum anti-parasite medicine of new generation developed by Pfizer Inc. the nineties in 20th century, it is by the Avrmectin streptomyces strain biosynthesizing under the environment containing heptanaphthenic acid (CHC) suddenlyd change.Doractin belongs to Avermectins medicine, but there is the pharmacokinetic properties better than Avrmectin and effect, its parasiticide is in extensive range, in body Plasma Concentration high, eliminate slow (5.7 days doractin transformation period, 4.2 days Avrmectin transformation period), duration of efficacy is grown, without anaphylaxis etc.Doractin ratifies the insect repellent for animals as parasitic infections such as domestic animal gastrointestinal nematode parasites, young tiger lung worm, eye parasite, grub, suction lice, mange mite such as treatment ox, sheep, pigs by FDA (Food and Drug Adminstration) (FDA).
Doractin is identical with the expelling parasite mechanism of Avrmectin, it is all the realization that is used for by reinforcing gamma-amino butyric acid (GABA), GABA is a kind of inhibitory neurotransmitter, postsynaptic neuronal is mainly suppressed to conduct at brain GABA, GABA burst size increases, and the normal resting potential of postsynaptic cell is improved, and nerve is difficult to stimulus delivery to muscle, muscle can not be shunk, cause parasite benumb and be purged.Housefly is compared with Mammals, and its sensitivity to avermectins increases by 600 ~ 700 times, and has very high selectivity, and under normal using dosage, security is better.
Criticize in cultivation and fermentation technique at existing doractin, mostly only adopt pH, DO, temperature etc. as the foundation of control strategy and means.These parameter majority of cases only can reflect performance or the operational condition of equipment, and can not be real-time, the physiological status that reflects Duola streptomycete really.Doractin fermenting process belongs to oxygen consumption fermentation, and growth and product that especially the oxygen consumption level in early stage controls producing bacterial strain are formed with important impact.In doractin fermenting process, must provide suitable stirring and ventilation, required meta-bolites could be bred and accumulate to thalline.In addition, be different in the oxygen requirement of the thalline in different fermentations stage, the size of the oxygen delivery capacity of fermented liquid directly affects the activity of the enzyme of microorganism, pathways metabolism and Product yields.Therefore studying oxygen supply size on the impact of fermentation and control enhancing productivity, improving quality product etc. all significant.
General oxygen consumption fermenting process all controls higher oxygen supply with the generation avoiding oxygen to limit, in this case can with dissolved oxygen concentration (DissolvedOxygen, be called for short DO) characterize Oxygen supplied level, can effective control DO by controlling mixing speed and air flow quantity.Dissolved oxygen level is by oxygen supply speed (OTR) and the impact of oxygen consumption rate (OUR) two aspect.Wherein the influence factor of OTR mainly contains rheological characteristics and the operating parameters of fermented liquid, such as flow, mixing speed, stirring arm type etc.With DO and OTR unlike, OUR is a typical physiological parameter, can reflect the real oxygen consumption situation of Duola streptomycete.As a rule, dissolved oxygen level generally can control more than critical dissolved oxygen by fermentation, otherwise oxygen supply will become restrictive factor, and OUR will change along with the change of OTR, and this situation is generally unfavorable for fermenting and carries out.
Summary of the invention
It is the doractin fermentation method for producing of controling parameters based on oxygen consumption rate OUR that the technical problem to be solved in the present invention is to provide a kind of, adopt two sections of OUR control strategies, with higher OUR, mycelia is grown fast early stage and produces fast to tire, later stage controls rational OUR level, minimizing consumption is sugared and mycelia is aging, promote the quick increase of doractin synthesis, and maintain long Fast back-projection algorithm speed, the doractin fermentation yield of 260 hours is up to 1934ug/ml.
The present invention is achieved through the following technical solutions:
Based on the doractin fermentation method for producing that oxygen consumption rate OUR is controling parameters, comprise doractin fermenting process, calculate the oxygen consumption rate OUR of thalline during the fermentation in real time, the oxygen consumption rate OUR value that 0-50 hour early stage controlled thalline by mixing speed and ventilation oxygen-supplying adjustment is 28-30mmol/l/h, and 50-260 hour afterwards differentiation fermentation stage adds the oxygen consumption rate OUR value controlling thalline continuously by mixing speed, ventilation oxygen-supplying and ammonium sulfate be 18-21mmol/l/h;
Wherein F
infor charge flow rate, unit mmol/L/hr; V is fermentating liquid volume; O
2in,
-o
2outfor oxygen mole concentration in air inlet and tail gas; N
2in,
-n
2outfor nitrogen volumetric molar concentration in air inlet and tail gas.
The further improvement project of the present invention is, oxygen consumption rate OUR calculates and adopts Shun's space permanent horizontal tail makings spectrometer to carry out real-time online collection analysis to air inlet and tail gas.
The further improvement project of the present invention is, it is 0.038g ± 0.006g/lh that ammonium sulfate adds speed.
The present invention compared with prior art, has following obvious advantage:
Criticize in cultivation and fermentation technique at existing doractin, mostly only adopt pH, DO, temperature etc. as the foundation of control strategy and means.These parameter majority of cases only can reflect performance or the operational condition of equipment, and can not be real-time, the physiological status that reflects Duola streptomycete really.The present invention by mass spectrometer in doractin fermenting process to the on-line analysis of tail gas and software package in line computation, determine one and be used to guide doractin fermentation processes method, the optimization doractin fermentating controling process key parameter obtained.Adopt two sections of OUR control strategies, with higher OUR, mycelia is grown fast early stage and produces fast to tire, later stage controls rational OUR level, minimizing consumption is sugared and mycelia is aging, promote the quick increase of doractin synthesis, and maintaining long Fast back-projection algorithm speed, the doractin fermentation yield of 260 hours is up to 1934ug/ml.
Accompanying drawing explanation
Fig. 1 is OUR change curve under different Oxygen supplied level in early stage.
Fig. 2 is the Product formation variation diagram under different oxygen consumption rate level in earlier stage.
Fig. 3 is that OUR-A controls lower differentiation thalli morphology figure after 96 hours.
Fig. 4 is that OUR-B controls lower differentiation thalli morphology figure after 96 hours.
Fig. 5 is that OUR-C controls lower differentiation thalli morphology figure after 96 hours.
Fig. 6 is OUR-B later stage in early stage different OUR change curve.
Fig. 7 is the Product formation variation diagram under OUR-B later stage in early stage different oxygen consumption rate level.
Embodiment
One, materials and methods
1, bacterial classification and substratum
Produce bacterial strain: Duola streptomycete JT-01, is stored in Jiangsu prestige and insults biochemical company limited
Inclined-plane/dull and stereotyped seed culture medium:
Starch 0.6%, yeast extract 0.4%, magnesium sulfate 0.05%, dipotassium hydrogen phosphate 0.05%, sodium-chlor 0.05%, SODIUMNITRATE 0.1%, agar powder 1.5%; PH7.
Shake-flask seed substratum:
Starch 2%, soybean cake powder 1%, dipotassium hydrogen phosphate 0.2%, sodium-chlor 0.1%, calcium carbonate 0.2%; PH7.
Fermention medium:
Starch 15%, soybean cake powder 1.2%, yeast extract 0.7%, dipotassium hydrogen phosphate 0.5%, sodium-chlor 0.06%, the heptanaphthenic acid sodium 3% of 10% concentration; PH7.
2, instrument and reagent
Instrument: fermentor tank Shanghai Guoqiang biochemistry equipment limited liability company 15L and 50L fermentor tank; The permanent horizontal tail makings spectrometer of Shun's space and analysis software; 722 type ultraviolet-visible pectrophotometers; Rotary shaker.
3, cultural method
Doractin fermentation adopts three grade fermemtation, ferments comprising secondary seed.
The bacterial classification spore inoculating needle of preservation or aseptic bamboo let are evenly coated on inclined-plane/plate culture medium, under 28 DEG C and 40% relative humidities, cultivate 5-7 days.
In 500ml shaking flask, add 100ml seed culture medium, after sterilizing, access 3-4ml spore suspension, at 28 DEG C, under 240rpm, cultivate 24-48 hour.
In 500ml Erlenmeyer flask, add 100ml fermention medium, access 8ml seed liquor, at 28 DEG C, cultivates 13 days under 240rpm.
4, measuring method:
Reducing sugar test: DNS method.
Biomass estimation: determined off-line adopts volumetric method, and 10mL fermented liquid is placed in centrifuge tube, and the centrifugal 15min of 3000rpm, pours centrifugal supernatant into graduated cylinder, goes out the volume of fermented liquid according to the volume computing of supernatant.
Titration: adopt state-promulgated pharmacopoeia method.
PH, DO on-line determination: adopt the high temperature resistant electrode of MettlerToledo to carry out on-line determination.
Temperature: platinum temperature electrode on-line determination.
The mensuration of oxygen and nitrogen in air inlet and tail gas: adopt Shun's space permanent horizontal tail makings spectrometer to carry out real-time online collection analysis to the air inlet in fermenting process and tail gas.
Oxygen consumption rate OUR measures: the calculating of OUR is by calculating the analytical data of fermentation tail gas.With rare gas element N in air inlet and tail gas
2maintain constant equilibrium establishment equation, the calculation formula of trying to achieve OUR is as follows:
Wherein F
infor charge flow rate, unit mmol/L/hr; V is fermentating liquid volume, units/kg; O
2in,
-o
2outfor oxygen mole concentration in air inlet and tail gas; N
2in,
-n
2outfor nitrogen volumetric molar concentration in air inlet and tail gas.
Two, result and discussion
1, earlier fermentation (0-50 hour) oxygen consumption rate controls the synthesis with doractin
In 50L fermentor tank, carrying out doractin fermentation, studying the oxygen consumption rate OUR level of thalline and the impact of Product formation speed by regulating Oxygen supplied level.This research is first in the fermenting process of doractin, by adjustment ventilation flow rate and mixing speed, control different Oxygen supplied levels, have studied and produce the metabolic condition of bacterium under different oxygen consumption rate state, by adding the remaining sugar concentration that glucose remains certain in whole process, whole fermenting process is made to be in non-saccharide restriction state.
Regulate and control the doractin earlier fermentation Oxygen supplied level of 0-50 hour by the adjustment of mixing speed and air flow, control its oxygen consumption rate OUR respectively respectively at 38-41mmol/l/h (OUR-A), 28-30mmol/l/h (OUR-B) and 18-22mmol/l/h (OUR-C).Comparing on three kinds of control strategy OUR basic change rule bases, the data of getting three batch fermentations compare analytical results and see Fig. 2, table 1.Find out from result, when OUR peak value is 38-41mmol/l/h, fermentation initial potency is 40ug/ml, puts tank and tires as the specific growth rate of 1395ug/ml, 0-50h is 0.0189h
-1, arriving maximum bacterium dense (PMV56%) sugar consumption speed is 0.42g/l/h; As OUR peak value control 28-30mmol/l/h, though initial potency only has 22ug/ml, finally tire as 1583IU/ml, the specific growth rate of 0-50h is 0.0167h
-1, arriving maximum bacterium dense (PMV52%) sugar consumption speed is 0.39g/l/h; When OUR peak value control 18-22mmol/l/h lower level, its initial potency and all low above two kinds of control strategies of finally tiring, the specific growth rate in early stage only has 0.0104h
-1, arriving maximum bacterium dense (PMV46%) sugar consumption speed is 0.28g/lh, and tunning synthesis rate is starkly lower than other two kinds of oxygen consumption rate control conditions, and final tunning only has 840ug/ml, can caused by energy metabolism changes.In a word, prior fermentation OUR is controlled at certain limit (28-30mmol/lh), the distribution of metabolic fluxes, particularly primary metabolite and secondary metabolism may be conducive to and divide pairing fermentation to produce material impact.
The doractin sugar fermentation consumption of table 1 earlier fermentation (0-50) OUR control strategy, cell concentration fermentation unit
As can be seen from Figure 1, the oxygen consumption rate OUR of the higher thalline of Oxygen supplied level is also higher.But, at high oxygen consumption rate 38-41mmol/l/h(OUR-A) fermentation condition under, after proceeding to 40 hours, the wear rate OUR of oxygen presents quick downward trend, this is mainly relevant with the excessive differentiation of thalline in fermenting process, and this is because too high OUR has impelled the premature aging of mycelia, also demonstrate that this point by microscopic examination: early stage, the high aerobe fermentation that supplies was to 96 hours (see figure 3)s, mycelia is not easily colored and mycelia is height breaking state, and fermentation broth viscosity is very low.And control at 28-30mmol/l/h(OUR-B at oxygen consumption rate) in situation, after the differentiation of 96 hours correspondences, mycelia is healthy and strong, mycelia is longer, dyeing is dark, at this moment the very fast (see figure 4) of Product formation speed, but at low oxygen consumption rate at 18-22mmol/l/h(OUR-C) under control condition, the differentiation of 96 hours mycelia is more late, and mycelia is thinner simultaneously, dye shallow (see figure 5), and corresponding Product formation speed is also starkly lower than high oxygen consumption rate control batch.
, oxygen consumption rate controls and the synthesis of doractin after doractin later stage (50-260 hour) differentiation
In doractin fermenting process, the maintenance of later stage oxygen consumption rate, for Product formation important, especially plays keying action in the energy supply of synthesis and the rate of differentiation control of mycelia.Therefore this study tour fermentation culture late-stage differentiation stage is added by ammonium sulfate stream and controls the impact of different oxygen consumption rate levels on doractin fermentation synthesis.
According to investigation experimental result above, the oxygen consumption rate in early stage is controlled at 28-30mmol/l/h(OUR-B), later stage controls the respiratory metabolism vigor of thalline respectively at 25-28mmol/l/h(OUR-E by the flow rate regulation of adding of quick-acting nitrogenous source), 18-21mmol/l/h (OUR-F) and 10-14mmol/l/h (OUR-G) three levels, OUR change curve is shown in Fig. 6, and accompanying drawing 7 and table 2 are shown in doractin fermentation synthesis.
Doractin fermentating metabolism in table 2 later stage different oxygen consumption rate situation
In the adjustment of doractin earlier fermentation by rotating speed and air flow, control oxygen consumption rate at 28-30mmol/l/h, the metabolism and growth of three batches is more consistent, the differentiation phase is entered after 50 hours, along with mycelial differentiation fracture, the wear rate of oxygen significantly declines, in order to stablize rational oxygen consumption rate OUR, we research and analyse through a large amount of, find to add the maintenance that can promote oxygen consumption rate well by necessarily adding speed ammonium sulfate.Also can find out from the building-up process variation diagram (Fig. 7) of product, when synthesis phase controls oxygen consumption rate at 25-28mmol/l/h, the synthesis rate before 180 hours that ferments is higher, but synthesis rate afterwards reduces gradually, the fermentation yield of 260 hours is 1740ug/ml, oxygen consumption rate is under 18-21mmol/l/h state, and it is best that the synthesis rate of product maintains, and the doractin fermentation yield of 260 hours has been up to 1934ug/ml.As the horizontal 10-14mmol/l/h of the oxygen consumption rate that later stage maintenance is lower, the synthesis of doractin is obviously restricted, and final unit only has 1495ug/ml.
Based on the above fact, we adopt two sections of OUR control strategies through doractin novel process, early stage uses higher OUR(28-30mmol/l/h) mycelia is grown fast and produces fast to tire, later stage controls rational OUR(18-21mmol/l/h) level, minimizing consumption is sugared and mycelia is aging, promote the quick increase of doractin synthesis, and maintain long Fast back-projection algorithm speed.
Claims (3)
1. be the doractin fermentation method for producing of controling parameters based on oxygen consumption rate OUR, comprise doractin fermenting process, it is characterized in that: the oxygen consumption rate OUR calculating thalline during the fermentation in real time, the oxygen consumption rate OUR value that 0-50 hour early stage controlled thalline by mixing speed and ventilation oxygen-supplying adjustment is 28-30mmol/l/h, and 50-260 hour afterwards differentiation fermentation stage adds the oxygen consumption rate OUR value controlling thalline continuously by mixing speed, ventilation oxygen-supplying and ammonium sulfate be 18-21mmol/l/h;
Wherein F
infor charge flow rate, unit mmol/L/hr; V is fermentating liquid volume; O
2in,
-o
2outfor oxygen mole concentration in air inlet and tail gas; N
2in,
-n
2outfor nitrogen volumetric molar concentration in air inlet and tail gas.
2. the doractin fermentation method for producing being controling parameters based on oxygen consumption rate OUR according to claim 1, is characterized in that: oxygen consumption rate OUR calculates and adopts Shun's space permanent horizontal tail makings spectrometer to carry out real-time online collection analysis to air inlet and tail gas.
3. the doractin fermentation method for producing being controling parameters based on oxygen consumption rate OUR according to claim 1, is characterized in that: it is 0.038g ± 0.006g/lh that ammonium sulfate adds speed.
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| PCT/CN2015/094999 WO2017049751A1 (en) | 2015-09-22 | 2015-11-19 | Dectomax fermentation production method on basis of using oxygen uptake rate (our) as control parameter |
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| CN113403193A (en) * | 2021-06-18 | 2021-09-17 | 华东理工大学 | Multistage continuous fermentation system |
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| CN110468167B (en) * | 2018-05-04 | 2022-12-27 | 上海凯赛生物技术股份有限公司 | Method for producing 1, 5-pentanediamine by fermentation |
| CN109022623A (en) * | 2018-07-20 | 2018-12-18 | 华东理工大学 | Method based on the on-line parameter CER regulation aspergillus niger transferred species time |
| CN115948622A (en) * | 2022-09-22 | 2023-04-11 | 北京蓝晶微生物科技有限公司 | Microbial fermentation control method, device, system, equipment and medium |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103642870A (en) * | 2013-12-11 | 2014-03-19 | 河北欣港药业有限公司 | Fermentation production method of rifamycin SV based on oxygen uptake rate OUR used as control parameter |
| CN104561180A (en) * | 2014-12-26 | 2015-04-29 | 宁夏泰瑞制药股份有限公司 | Culture mediums for producing doramectin through fermentation of mutant streptomyces avermitilis and material supplement method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103642870A (en) * | 2013-12-11 | 2014-03-19 | 河北欣港药业有限公司 | Fermentation production method of rifamycin SV based on oxygen uptake rate OUR used as control parameter |
| CN104561180A (en) * | 2014-12-26 | 2015-04-29 | 宁夏泰瑞制药股份有限公司 | Culture mediums for producing doramectin through fermentation of mutant streptomyces avermitilis and material supplement method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113403193A (en) * | 2021-06-18 | 2021-09-17 | 华东理工大学 | Multistage continuous fermentation system |
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