CN105586374A - Process for producing doramectin with carbohydrate supplementation based on metabolic parameter reducing sugar - Google Patents
Process for producing doramectin with carbohydrate supplementation based on metabolic parameter reducing sugar Download PDFInfo
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Abstract
The invention relates to the field of biological fermentation technology, and concretely provides a process for producing doramectin with carbohydrate supplementation based on metabolic parameter reducing sugar. Real-time monitoring of concentration of reducing sugar is carried out in a fermentation process, after primary metabolism ends, when the concentration of total sugar decreases to 1.5-2 wt%, and the concentration of reducing sugar decreases to 0.3-1.0 wt%, fed-batch and carbohydrate supplementation are carried out. Finally, when the vitality of bacteria decreases, and growth in unit is slow, a pot is discharged. The fed-batch and the carbohydrate supplementation are carried out after the metabolic transformation ends and fermentation enters a secondary metabolism period, that is the fed-batch and the carbohydrate supplementation are carried out at an entire antibiotic production stage, so that 'glucose effect' is decreased, product unit is increased, and at the same time production cost is reduced. The technology is mature, and is suitable for industrial large-scale production.
Description
Technical field
The present invention relates to technical field of biological fermentation, be specifically related to a kind of based on metabolizing parameters reduced sugar feeding glucose fermentation production doractin technique.
Background technology
Doractin (Doramectin, DRM), for macrolides antiparasitic agent of new generation, a kind of Avermectins antibiotic generating taking cyclohexane-carboxylic acid (cyclohexanecarboxylicacid, CHC) as precursor during the fermentation by the new bacterial strain of Avid kyowamycin (StreptomycesavermitilisstrainNEAU1069) of genetic recombination. Doractin is the inside and outside double agent of killing, and nematode, arthropod are all had to good repelling and killing efficacy, and with commercially available ivermectin series products comparison, to hold time in wider general, the blood concentration peak of its anti parasitic longer, the half-life is also relatively long. And doractin efficiency time is longer in animal body, be to be considered at present one of classic anti-parasite medicine of AVM family.
The production of doractin at present is mainly undertaken by the method for biofermentation, main using cornstarch as its main fermenting carbon source, but fermentation period is long, and unit is on the low side, and power cost is higher, the corresponding increase of fermentation costs.
Be seeded to by cultivating through inclined-plane with seed culture gained seed liquor the fermentation tank that fermentation medium is housed, reduced sugar control is that thalline produces plain key index, along with fermentation initial stage reduced sugar consumes fast, grow normally required when the quick-acting carbon sources in culture medium can not meet thalline, now fermentation enters the metabolism transition period, concentration of reduced sugar further declines, and in this process, thalline starts progressively to induce the enzyme system relevant to producing element.
When thalline has completed metabolism conversion, while having entered the slow stage of imitating carbon source of utilization completely, this indicates and is subject to the thalline activities of the enzyme systems of glucose effect to start to recover, and also shows that thalline enters the plain stage of product simultaneously. When the concentration of reduced sugar that characterizes thalline vigor drops to after a certain numerical value, can meet the growth of thalline cometabolism required, can produce to greatest extent again element.
If now mend after metabolism conversion, sugared too high although can to increase substantially bacterium dense, promote the growth of thalline, but there is certain inhibitory action to producing plain aspect, this is to produce a large amount of reduced sugars while being utilized by thalline fast decoupled as carbon source due to liquefaction cornstarch or maltodextrin, often the enzyme in other metabolic pathways (comprising antibiotic synzyme and other enzymes system) is checked or inhibitory action to i.e. " glucose effect ".
By detecting the concentration of reduced sugar at fermentation initial stage, control the Degree of Liquefaction of cornstarch, be both beneficial to thalline and utilized quick-acting carbon sources to complete primary metabolite mycelial growth, be beneficial to again thalline and start to utilize slow effect carbon source to enter cometabolism; But too much the degraded of effect carbon source can produce a large amount of quick-acting carbon sources late, be unfavorable for that cometabolism produces element, can reduce the impact of reduced sugar on cometabolism by reducing original corn amount of starch.
Method report based on metabolizing parameters reduced sugar benefit sugar raising fermentation unit production doractin technique is also few at present. The technique of mending sugar raising fermentation unit in prior art based on metabolizing parameters OUR, depends on tail gas checkout equipment, only has at present laboratory to use, and factory does not generally match this equipment, is unfavorable for promoting, and is not suitable for industrial scale applications.
This product produces element to concentration of reduced sugar sensitivity, if earlier fermentation concentration of reduced sugar is too high or too low, can cause fermentation starting unit lower; Later stage concentration of reduced sugar is too high or too low, and Hui Shi every day unit increases slack-off, and the cycle is elongated; Therefore, in feeding glucose fermentation process, need to determine according to sweat index speed and the consumption of feed supplement, if feedback index is not obvious or clash according to feed supplement time and speed and thalline product element, will bring serious negative consequence to fermentation results.
Summary of the invention
For problems of the prior art, the present invention mends sugar operation by the value based on metabolizing parameters reduced sugar in thalline sweat, provides a kind of raising fermentation unit to produce doractin technique.
Described one is mended sugar based on metabolizing parameters reduced sugar and is produced doractin technique, comprises following processing step:
(1), will cultivate through inclined-plane and the seed liquor of seed culture gained is seeded in the fermentation tank that fermentation medium is housed;
(2), concentration of reduced sugar in sweat Real-Time Monitoring fermentation tank, after selecting primary metabolite to finish, total sugar concentration drops to 1.5-2%wt, concentration of reduced sugar is reduced to 0.3wt% ~ 1.0wt% simultaneously, starts stream and adds and mend sugar;
(3) fermentation later stage unit increasess slowly, and occurs automyophagy, when product starts to discharge to born of the same parents in born of the same parents, puts tank.
Further, preferred steps (2) total sugar concentration drops to 1.5-2%wt, when concentration of reduced sugar is reduced to 0.5wt% simultaneously, starts stream and adds benefit sugar.
Wherein, the condition of culture of the described slant medium of step (2) is: inoculation, to slant medium, under 25 DEG C ~ 30 DEG C conditions, preferably, under 27 DEG C ~ 29 DEG C conditions, is cultivated 6 ~ 8 days, obtain spore; Slant medium contains (wt%): sweet mellow wine 1-3, and soybean cake powder 1-3, agar 1-3, surplus is distilled water, and the pH value of slant medium is adjusted to 6.8-7.2, preferably the pH value of slant medium is adjusted to 7.0-7.2.
The condition of culture of the described seed culture medium of step (2) is: will cultivate the spore access seed culture medium of gained through inclined-plane, in 25 DEG C ~ 30 DEG C, preferably 27 ~ 29 DEG C, shaking speed is 220 ~ 250r/min, cultivates 40h ~ 50h; Seed culture medium contains (wt%): cornstarch 1-3, and glucose 0.3-0.7, soybean cake powder 1-2, cottonseed meal 1-2, surplus is running water, and the pH value of seed culture medium is adjusted to 6.8-7.2, preferably the pH value of seed culture medium is adjusted to 7.0-7.2.
Preferably, the inoculum concentration that seed liquor is accessed fermentation tank by step (2) is 8-12%((V)); Fermentation culture conditions is: cultivation temperature is at 25 ~ 30 DEG C, preferably 27-29 DEG C, and pressure 0.04-0.06MPa, DO is controlled at 30%-100%, under the condition of rotating speed 200-600rpm, cultivates 432-480h; Fermentation cylinder for fermentation culture medium contains (wt%): cornstarch 10-12, soybean cake powder 1-2, cottonseed meal 1-2, dusty yeast 0.5-1, a-amylase 0.01-0.02, dipotassium hydrogen phosphate 0.2-0.4, sodium chloride 0.1-0.2, magnesium sulfate 0.3-0.5, calcium carbonate 0.5-0.8, bubble enemy 0.1, surplus is running water, described fermentation medium regulates pH6.8-7.2 with 5%NaOH solution, preferably pH value is adjusted to 7.0-7.2.
Further, the fermentation medium of preferred steps (2) fermentation tank is first reduced to 8wt% by original corn starch from 12wt%, and by controlling cornstarch Degree of Liquefaction, initial fermentation reducing sugar concentration is maintained between 1.8-2wt%.
Described one is mended sugar based on metabolizing parameters reduced sugar and is produced doractin technique, it is characterized in that, fermentation later stage total reducing sugar is reduced to 1.5-2%, when reduced sugar is reduced to 0.5%, start stream and add benefit sugar, described stream adds mends sugared operation, be according to consume every day total Standard for Sugars of 0.5% and every day volume volatile quantity, it is 20%-60% liquefaction cornstarch or maltodextrin that stream adds concentration.
Preferably, benefit sugar of the present invention is liquefaction cornstarch or maltodextrin.
In the fermentation later stage, thalline vigor declines, and unit increasess slowly, and occurs automyophagy, when product starts to discharge to born of the same parents in born of the same parents, shows to put tank.
The present invention is chosen in metabolic conversion and finishes, in the time that fermentation enters the cometabolism phase, to produce the element phase completely, and stream adds mends sugar, has weakened " glucose effect ", and product unit is improved, and has reduced production cost simultaneously. Technology maturation of the present invention, is applicable to industrial scale and produces.
Technical scheme of the present invention is based on the control of metabolizing parameters reduced sugar, and by sweat Real-Time Monitoring concentration of reduced sugar, stream adds mends sugar raising fermentation unit, detection method is easy, be the conventional detection method that laboratory and factory all possess, be applicable to industrialization and generate, cost is low. Compared with prior art, amount by control reduced sugar is more direct, carry out controlled fermentation process streams based on metabolizing parameters reduced sugar and add benefit sugared time and speed, can significantly reduce because equipment feedback index is not obvious or lag behind the probability that causes feed supplement time and speed and thalline product element to clash.
The invention provides one and produce doractin technique based on metabolizing parameters reduced sugar feeding glucose fermentation, reasonable in design, fermentation titer improves approximately 30% compared with not mending sugared fermentation titer; Cost is reduced to 2500 yuan/kg from 3300 yuan/kg, makes a price reduction approximately 25%.
Detailed description of the invention
By specific embodiment, content of the present invention is further explained below. In invention, reduced sugar detection method adopts laboratory and factory's conventional detection method, as: after excessive Fehling test solution redox, the Cu in remaining Fehling test solution2+With KI reduction, then use Na2S2O3The I that standard liquid titration is separated out2, can calculate the quality of copper according to sample and the volume of the blank standard liquid consuming, then the content of the reducing sugar of asking of tabling look-up.
The Avermectins antibiotic that doractin of the present invention generates taking cyclohexane-carboxylic acid as precursor during the fermentation by the new bacterial strain of Avid kyowamycin of genetic recombination.
Medium component:
Preparation slant medium (wt%): sweet mellow wine 2, soybean cake powder 2, agar powder 2; Surplus is distilled water, pH7.0-7.2, and carry out sterilizing.
Preparation seed culture medium (wt%): cornstarch 2, glucose 0.5, soybean cake powder 1, cottonseed meal, surplus is running water, 5%NaOH solution regulates pH6.8-7.2.
Preparation fermentation medium (wt%): cornstarch 12, soybean cake powder 1, cottonseed meal 1, dusty yeast 0.5, a-amylase 0.02, dipotassium hydrogen phosphate 0.4, sodium chloride 0.1, magnesium sulfate 0.4, calcium carbonate 0.7, bubble enemy 0.1, surplus is running water, 5%NaOH solution regulates pH6.8-7.2.
Use medium component:
(1), inclined-plane is cultivated: inoculation, to fresh inclined-plane, is cultivated 8 days at 28 DEG C;
(2), seed culture: by step (1) gained spore access seed culture medium, cultivation temperature 27-29 DEG C, cultivates 40-48h under the condition of shaking speed 220-260r/min;
(3), fermented and cultured: step (2) gained seed liquor is seeded to fermentation tank (50L tank, general 30 liters of seed culture mediums after sterilizing), inoculum concentration 10%, cultivation temperature 27-29 DEG C, pressure 0.05MPa, DO is controlled at more than 30%, rotating speed 250-500rpm.
Embodiment 1
12wt% cornstarch adds 0.02wt% amylase, 65 DEG C are incubated 40 minutes, initial concentration of reduced sugar is controlled between 1.8-2wt%, and now starch liquefacation degree, is beneficial to thalline and utilizes quick-acting carbon sources to complete primary metabolite mycelial growth, but the slow effect carbon source degraded more due to the later stage produces a large amount of quick-acting carbon sources, be unfavorable for that cometabolism produces element, later stage unit increasess slowly, and ferments and puts tank after 432 hours, the 900ug/ml that tires, in table 1.
Embodiment 2
8wt% cornstarch adds 0.02wt% amylase, 65 degree insulations 50 minutes, initial concentration of reduced sugar is controlled between 1.8-2wt%, now starch liquefacation degree, both being beneficial to thalline utilizes quick-acting carbon sources to complete primary metabolite mycelial growth, be beneficial to again thalline and start to utilize slow effect carbon source to enter cometabolism, can reduce the impact of reduced sugar on cometabolism by reducing original corn amount of starch; In the time that reduced sugar is reduced to 0.5wt% left and right, start every day to consume the total reducing sugar of 0.5wt% left and right, it is 30% liquefaction cornstarch that stream adds mass percentage concentration, ferment and put tank after 432 hours, the 1200ug/ml that tires, in table 1, compared with not mending sugared fermentation titer, improve 30%.
Embodiment 3
Processing method, with example 2, in the time that reduced sugar is reduced to 0.5% left and right, starts every day to consume the total reducing sugar of 0.5% left and right, and it is 30% maltodextrin that stream adds mass percentage concentration. Ferment and put tank after 432 hours, the 1200ug/ml that tires, compared with not mending sugared fermentation titer, improves 30% and sees the following form 1.
Table 1:
。
Below be only explanation of the invention; and be not used in limitation of the present invention; those skilled in the art are reading the amendment that can make as required any replaceability after this description to the present embodiment; as long as in thought of the present invention; anyly have the knack of this skill person; without departing from the spirit and scope of the present invention, when doing to change and retouching, the scope that therefore protection scope of the present invention ought define depending on accompanying claims is as the criterion.
Claims (6)
1. mend sugar based on metabolizing parameters reduced sugar and produce a doractin technique, comprise following processing step:
(1), will cultivate through slant medium and seed culture medium is cultivated the seed liquor of gained and is seeded in the fermentation tank that fermentation medium is housed;
(2), concentration of reduced sugar in sweat Real-Time Monitoring fermentation medium, after selecting primary metabolite to finish, total sugar concentration drops to 1.5 ~ 2%wt, when concentration of reduced sugar is reduced to 0.3wt% ~ 1.0wt% simultaneously, starts stream and adds and mend sugar;
(3) fermentation later stage unit increasess slowly, and occurs automyophagy, when product starts to discharge to born of the same parents in born of the same parents, puts tank.
2. method according to claim 1, is characterized in that, the condition of culture of the described slant medium of step (2) is: inoculation, to slant medium, under 25 DEG C ~ 30 DEG C conditions, is cultivated 6 ~ 8 days, obtain spore; Slant medium contains (wt%): sweet mellow wine 1-3, and soybean cake powder 1-3, agar 1-3, surplus is distilled water, and the pH value of slant medium is adjusted to 7.0-7.2.
3. method according to claim 1, is characterized in that, the condition of culture of the described seed culture medium of step (2) is: will cultivate through inclined-plane the spore access seed culture medium of gained, in 25 DEG C ~ 30 DEG C, shaking speed is 220 ~ 250r/min, cultivates 40h ~ 50h; Seed culture medium contains (wt%): cornstarch 1-3, and glucose 0.3-0.7, soybean cake powder 1-2, cottonseed meal 1-2, surplus is running water, and the pH value of seed culture medium is adjusted to 7.0-7.2.
4. according to method described in the arbitrary claim of claim 1 ~ 3, it is characterized in that, the inoculum concentration that seed liquor is accessed fermentation tank by step (2) is 8-12%(V); Fermentation culture conditions is: cultivation temperature is at 27-29 DEG C, pressure 0.04-0.06MPa, and DO is controlled at 30%-100%, under the condition of rotating speed 200-600rpm, cultivates 432-480h; Fermentation cylinder for fermentation culture medium contains (wt%): cornstarch 10-12, soybean cake powder 1-2, cottonseed meal 1-2, dusty yeast 0.5-1, a-amylase 0.01-0.02, dipotassium hydrogen phosphate 0.2-0.4, sodium chloride 0.1-0.2, magnesium sulfate 0.3-0.5, calcium carbonate 0.5-0.8, bubble enemy 0.1, surplus is running water, the pH value of described fermentation medium is 7.0-7.2.
5. according to method described in the arbitrary claim of claim 1 ~ 3, it is characterized in that, the fermentation medium of step (2) fermentation tank is first reduced to 8wt% by original corn starch from 12wt%, and by controlling cornstarch Degree of Liquefaction, initial fermentation reducing sugar concentration is maintained between 1.8-2wt%.
6. according to method described in the arbitrary claim of claim 1 ~ 3, it is characterized in that, the described stream of step (2) adds mends sugared operation, be according to consume every day total Standard for Sugars of 0.5% and every day volume volatile quantity, it is 20%-60% liquefaction cornstarch or maltodextrin that stream adds concentration.
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