CN105671110B - A method of producing Dalbavancin precursor A40926 - Google Patents
A method of producing Dalbavancin precursor A40926 Download PDFInfo
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- CN105671110B CN105671110B CN201510221758.2A CN201510221758A CN105671110B CN 105671110 B CN105671110 B CN 105671110B CN 201510221758 A CN201510221758 A CN 201510221758A CN 105671110 B CN105671110 B CN 105671110B
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Abstract
The invention discloses a kind of methods for producing Dalbavancin precursor A40926.It specifically discloses, during fermented and cultured, by flowing the yield for adding 10- methyl undecanoic acid or several 10- methylundecane acid salt solutions to improve Dalbavancin precursor A40926 into fermentation liquid.Method provided by the invention is easy to operate, significantly improves fermentation yield, reduces production cost, is suitable for industrialized production.
Description
Technical field
The present invention relates to field of biological pharmacy, and in particular, to a method of produce Dalbavancin precursor A40926.
Background technique
Dalbavancin (Dalbavancin) is that glycopeptide antibiotics and vancomycin of new generation, Ramoplanin belong to together
It is a kind of.This kind of antibiotic are for treating those most ticklish bacterium infections, such as methicillin-resistant S grape ball
Bacterium (MRSA) and methicillin resistance staphylococcus epidermis (MRSE).Experiment in vitro shows that Dalbavancin is in addition to clinical normal
The gram-positive bacteria bactericidal activity enhancing seen is outer, and half-life period is longer, and penetration into tissue is more preferable, and such patient's administration has more
Big flexibility.So far the preclinical and clinical studies show carried out, Dalbavancin are strongest to MRSA and MRSE activity
One of antibiotic, and do not cause significant dose-limiting adverse reaction.
Dalbavancin mechanism of action is identical as vancomycin and teicoplanin, inhibits G+The biosynthesis of bacterium cell wall, quilt
It is widely used as the drug for the treatment of Skin and soft tissue infection.Body it is inside and outside experiments have shown that, Dalbavancin is for G+Bacterium, including resistance to first
Oxygen XiLin staphylococcus aureus (MRSA), methicillin-sensitivity staphylococcus aureus (MSSA), coagulase-negative staphylococci (CoNS), hammer
Bacterium etc. has antibacterial activity.To resistance to G+Pathogen includes that penicillin resistant and ceftriaxone streptococcus pneumonia, teicoplanin are insensitive
CoNS, non-vanA type enterococcus are active；To G+Anaerobic bacteria is also active.Dalbavancin has unique pharmacokinetics
Matter, can every weekly interval medication.Currently, Dalbavancin is in the relevant Hematogenous infection for the treatment of conduit and Skin and soft tissue infection
Good effect has been achieved, has been ideal second generation glycopeptide class antibiosis with excellent antibacterial activity in vivo and safety
Element.Its precursor A40926 be by the village Ye Ye actinomyces (Nonomuraea)sp.ATCC39727 the natural sugar peptides antibiosis generated
Element.A40926 can obtain Dalbavancin after carrying out modifying for chemical structure.Food and drug administration (FDA) is in 2014 5
Have been approved by within 23rd Dalbavancin listing the moon.
Dalbavancin precursor A40926 is mainly produced by microbial fermentation at present, A40926 and its derivative knot
Structure formula is as follows:
。
Fermentation generates 5 main components: PA, PB, A, B0 and B1, and B0 and B1 are referred to as B component.PA, PB are dividing in fermentation liquid
When from incubating in alkaline environment for a long time in purification process, A, B can be converted into.Wherein, B0 group is divided into mainly having for A40926
Component to be imitated, is the key intermediate for synthesizing Dalbavancin, it is characterised in that fatty acid chain is Permethyl 99A base on aminoglucose,
After carrying out decomposed from the fatty acid of own cells film under the action of acyltransferase in A40926 biosynthesis, shape
Being connected on the amino of aminoglucose at acyl chain is principal element (the Factors influencing cell for causing this difference
fatty acid composition and A40926 antibiotic complex production in Nonomuraea sp. ATCC 39727)。
Report less, Italian Vicuron in terms of A40926 zymotechnique both at home and abroad at present
The fermentating formula nutritional ingredient of Pharmaceuticals drugmaker report is simple, and spawn activity is not strong, and fermentation unit is only
128mg/L。
Beltrametti etc. is the study found that Valine is the potential precursor of branch's acyl chain of B0 component, in fermentation training
The ratio of B0 component in product can be increased by supporting addition Valine in base, while improve the total output (Valine of A40926
Influences Production and Complex Composition of Glycopeptide Antibiotic
A40926 in Fermentations of Nonomuraea sp. ATCC 39727。J Antibiot (Tokyo). 2004
Jan;57 (1): 37-44), but the limited only 220mg/L of fermentation unit increase rate.
CN 201010164616.4 discloses a kind of by adjusting carbon nitrogen source ingredient and proportion in fermentation medium, optimization
The method of the fermentation parameters such as cultivation temperature, pH improves the fermentation yield of A40926, the fermentation of method disclosed in the patent A40926
Unit may be up to 336mg/L.
The zymotechnique that CN103060405A discloses a kind of optimization flows during the fermentation plus glucose, peptone and L-
Valine, fermentation unit are up to 720mg/L, and this method substantially increases the fermentation unit of A40926 to a certain extent,
But still there are feed supplement specific aim is not strong, trivial operations, the low problem of tunning yield, it is therefore desirable to which further exploitation improves
The effective method of A40926 fermentation unit.
Summary of the invention
It is an object of the present invention to for deficiency existing for existing zymotechnique, it is easy to operate to provide one kind, at low cost,
It is suitble to industrialized production, the zymotechnique of efficient Dalbavancin precursor A40926.
The present invention provides a kind of methods for producing Dalbavancin precursor A40926, including, during the fermentation to fermentation
10- methyl undecanoic acid or its salt are added in culture medium.
In the present invention, produce Dalbavancin precursor A40926 method, including, during the fermentation by stream plus in a manner of to
10- methyl undecanoic acid or its salt are added in fermentation medium.
In one embodiment, it is preferable that the method for production Dalbavancin precursor A40926, including, during the fermentation with stream
The mode added adds 10- methyl undecanoic acid or its salt into fermentation medium.
Further, it is preferable that the method for production Dalbavancin precursor A40926, including, after 24 ~ 48h of fermented and cultured, in
Flow velocity in every liter of fermentation liquid with 0.03 ~ 0.07ml/h is flowed into fermentor plus the methyl oleate solution of 10- methyl undecanoic acid,
Until fermentation ends.In general, when ferment 120h after, when the concentration of Dalbavancin precursor A40926 no longer increases, stop fermentation, i.e.,
Think fermentation ends.
Further, it is preferable that the concentration of the methyl oleate solution of the stream plus 10- methyl undecanoic acid is 40% ~ 60%
(w/w)。
In another embodiment, it is preferable that production Dalbavancin precursor A40926 method, including, fermented and cultured 24 ~
After 48h, is flowed with the flow velocity of 0.1 ~ 0.3 ml/h into fermentor in every liter of fermentation liquid and adds 10- methylundecane acid salt solution,
Until fermentation ends.In general, when ferment 120h after, when the concentration of Dalbavancin precursor A40926 no longer increases, stop fermentation, i.e.,
Think fermentation ends.
Further, it is preferable that the concentration of the stream plus 10- methylundecane acid salt solution is 5 ~ 15% (w/v), the 10-
Methylundecane hydrochlorate is 10- methyl undecanoic acid sodium, 10- methyl undecanoic acid potassium, 10- methyl undecanoic acid ammonium or it is any
Two or three of mixture.
In the above method of the present invention, it is preferable that after 24 ~ 48h of fermented and cultured, when biomass PMV reaches 20% or more, open
Begin stream plus 10- methyl undecanoic acid or its salt, until fermentation ends, wherein the biomass PMV is defined as: take 10ml fermentation liquid
It is placed on 3000rpm in graduated centrifuge tube and is centrifuged 15min, pouring out supernatant volume is V, then PMV=(10-V)/10.
In the above method, further, it is preferable that fermentation temperature is 24 ~ 28 DEG C, and pressure is 0.04 ~ 0.06Mpa, ventilatory capacity
For 0.5 ~ 1.5VVM, revolving speed is 100 ~ 250rpm.
In the present invention, the strain of the production A40926 is to be capable of fermenting and producing A40926's described in the routine of this field
Strain, the preferably village Ye Ye actinomyces, it is further preferred that the strain is the village Ye Ye actinomyces actinomyces ATCC 39727
(Nonomuraea. sp.ATCC39727).
In the present invention, the method for the production Dalbavancin precursor A40926 further includes the steps that seed culture, will produce
The strain seed of A40926 is inoculated into seed culture medium, carries out seed culture.Ability can be used in the seed culture medium
The preparation method of the conventional use of fluid nutrient medium in domain, the preferably described seed culture medium is as follows: glucose 10g/L, maltodextrin
25g/L, yeast extract 5g/L, soybean cake powder 20g/L, magnesium sulfate 1g/L, dipotassium hydrogen phosphate 1g/L, calcium carbonate 2g/L,
PH7.0。
Suitable seed culture medium is prepared, 26-30 DEG C is cooled to after 120 DEG C of sterilizing 30min, by seed culture medium volume ratio
The inoculum concentration of 0.3-1% accesses the shake-flask seed in 48h kind age, then 26-30 DEG C of 48 ~ 72h of culture.
In the present invention, the fermentation medium of the fermenting and producing Dalbavancin precursor A40926 for this field routine institute
The fermentation medium that the strain of the production A40926 said uses, preferably the fermentation medium preparation method are as follows:
Glucose 10g/L, maltodextrin 25g/L, soluble starch 25g/L, yeast extract 5g/L, peptone 5g/L,
Soybean cake powder 30g/L, magnesium sulfate 0.5g/L, calcium carbonate 2g/L, pH 7.0.
Suitable fermentation medium is prepared, 24 ~ 28 DEG C are cooled to after 120 DEG C of sterilizing 30min, by fermentation medium volume ratio
5 ~ 10% inoculum concentration accesses the trophosome inoculum in seed culture medium, and control temperature is at 24 ~ 28 DEG C in fermentation process, control
Pressure controls revolving speed in 100 ~ 250rpm, dissolved oxygen electrode is supervised online in 0.5 ~ 1.5VVM in 0.04 ~ 0.06Mpa, control ventilation
It surveys, to ensure dissolved oxygen in 30% or more (assuming that the initial dissolved oxygen of fermentor is 100%).
After 24 ~ 48h of fermented and cultured, when biomass PMV (take 10ml fermentation liquid be placed in graduated centrifuge tube 3000rpm from
Heart 15min, pouring out supernatant volume is V, then PMV=(10-V)/10) start stream plus 10- methylundecane when reaching 20% or more
Acid or its salt, until fermentation ends.In general, when ferment 120h after, when the concentration of Dalbavancin precursor A40926 no longer increases, stop
Only ferment.
Preferably, the feed process is the flow velocity in every liter of fermentation liquid with 0.03 ~ 0.07ml/h into fermentor
Stream adds the methyl oleate solution of 40 ~ 60% 10- methyl undecanoic acid, until fermentation ends.
Preferably, the feed process is to be flowed with the flow velocity of 0.1 ~ 0.3 ml/h into fermentor in every liter of fermentation liquid
Add 5 ~ 15% 10- methylundecane acid salt solution, until fermentation ends.The 10- methylundecane hydrochlorate is 10- methyl
Hendecanoic acid sodium, 10- methyl undecanoic acid potassium, 10- methyl undecanoic acid ammonium.
In the present invention, the preparation method of the methyl oleate solution of the 10- methyl undecanoic acid is as follows: will be suitable
10- methyl undecanoic acid and methyl oleate are dissolved in in-tank mixing, make ratio of the 10- methyl undecanoic acid in entire solution
40 ~ 60% (w/w), 120 DEG C of sterilizing 30min, for use.
In the present invention, the 10- methylundecane acid salt solution is formulated as follows: by suitable 10- methylundecane
Hydrochlorate is dissolved in water in tank, is configured to the 10- methylundecane acid salt solution of 5 ~ 15% (w/v), 120 DEG C of sterilizing 30min, to
With.
Using the concentration of HPLC detection Dalbavancin precursor A40926 in fermentation process, testing conditions are as follows:
Chromatographic column specification: 4.6mm*250mm*5 μm of C18 column, wavelength: 210nm, column temperature: 40 DEG C, flow velocity: 1ml/min,
Using gradient elution, mobile phase A phase: 0.02M potassium dihydrogen phosphate aqueous solution (W/V): acetonitrile=75:25 (V/V), Mobile phase B
Phase: 0.02M potassium dihydrogen phosphate aqueous solution (W/V): acetonitrile=62:38 (V/V),
| Time (min) | A phase | B phase |
| 0 | 100 | 0 |
| 29 | 0 | 100 |
| 31 | 100 | 0 |
| 36 | 100 | 0 |
Retention time: about 23min.
The present inventor is found surprisingly that 10- methyl undecanoic acid can be Dalbavancin precursor A40926 main component B0
Aminoglucose on the biosynthesis of fatty acid chain precursor is provided, to the ratio for increasing B0 component in product, while improving A40926
Total output significant effect.But this kind of precursor substance has a degree of toxicity to cell, excessively will affect microorganism and normally gives birth to
It is long.Therefore it needs through flow acceleration feed supplement appropriate, the inhibition to microorganism is reduced while promoting fermentation unit to improve.
10- methyl undecanoic acid water solubility is poor simultaneously, and methyl oleate is added to fermentation training as cosolvent or in a salt form
Be conducive to mix well in supporting, guarantee the supply of precursor substance.
The method that the present invention improves significantly improves fermentation yield, and 50% or more is improved compared with the technique currently reported,
Production cost is reduced, industrialized production is suitable for.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
And not meaning that has any restrictions to the present invention.Agents useful for same and raw material of the present invention are commercially available unless otherwise specified.
On the basis of common knowledge of the art, the optimum condition of above-mentioned various technical characteristics of the invention can be any
Composition obtains preferred embodiments of the invention.
The methyl oleate solution of stream plus 10- methyl undecanoic acid in 1 fermentation process of embodiment
300L seed culture medium is prepared in 500L seeding tank, is cooled to 28 DEG C after 120 DEG C of sterilizing 30min, is trained by seed
The shake-flask seed in the inoculum concentration access 48h kind age of base volume ratio 0.5% is supported, then 28 DEG C of culture 72h.
3500L fermentation medium is prepared in 5000L fermentor, is cooled to 26 DEG C after 120 DEG C of sterilizing 30min, by fermentation
Culture volume accesses trophosome inoculum in above-mentioned seed culture medium than 8% inoculum concentration, and control temperature is 24 in fermentation process
~ 28 DEG C, control pressure controls revolving speed in 100 ~ 250rpm, dissolved oxygen electricity in 0.5 ~ 1.5VVM in 0.04 ~ 0.06Mpa, control ventilation
Pole on-line monitoring, to ensure dissolved oxygen in 30% or more (assuming that the initial dissolved oxygen of fermentor is 100%).
Ferment 30h, and PMV reaches 24%, starts from the flow velocity in every liter of fermentation liquid with 0.05ml/h and flow into fermentor to add
The methyl oleate solution of 50% 10- methyl undecanoic acid, continuing fermentation stop hair after 120h when fermentation unit no longer increases
Ferment, fermentation liquid tune pH to 11.5,50 DEG C of water-bath 1h, filtering, it is 1.46g/L that HPLC, which detects fermentation unit,.
Stream plus 10- methylundecane acid sodium solution in 2 fermentation process of embodiment
350L seed culture medium is prepared in 500L seeding tank, is cooled to 28 DEG C after 120 DEG C of sterilizing 30min, is trained by seed
The shake-flask seed in the inoculum concentration access 48h kind age of base volume ratio 0.8% is supported, then 28 DEG C of culture 68h.
3500L fermentation medium is prepared in 5000L fermentor, is cooled to 27 DEG C after 120 DEG C of sterilizing 30min, by fermentation
Culture volume accesses trophosome inoculum in above-mentioned seed culture medium than 10% inoculum concentration, in fermentation process in fermentation process
Temperature is controlled at 24 ~ 28 DEG C, control pressure in 0.04 ~ 0.06Mpa, control ventilation in 0.5 ~ 1.5VVM, control revolving speed 100 ~
250rpm, dissolved oxygen electrode on-line monitoring, to ensure dissolved oxygen in 30% or more (assuming that the initial dissolved oxygen of fermentor is 100%).
Ferment 40h, and PMV reaches 25%, starts from the feed supplement stream into fermentor of the flow velocity in every liter of fermentation liquid with 0.2ml/h
Add 10% 10- methylundecane acid sodium solution, continuing fermentation stops fermentation, fermentation when fermentation unit no longer increases after 120h
Liquid tune PH to 11.5,50 DEG C of water-bath 1h, filtering, it is 1.54g/L that HPLC, which detects fermentation unit,.
Stream plus 10- methylundecane acid ammonium solution in 3 fermentation process of embodiment
600L seed culture medium is prepared in 1T seeding tank, 28 DEG C is cooled to after 120 DEG C of sterilizing 30min, by seed culture
The inoculum concentration of base volume ratio 0.3% accesses the shake-flask seed in 48h kind age, then 28 DEG C of culture 72h.
10000L fermentation medium is prepared in 20T fermentor, is cooled to 26 DEG C after 120 DEG C of sterilizing 30min, by fermentation training
The inoculum concentration for supporting base volume ratio 5% accesses trophosome inoculum in above-mentioned seed culture medium, controls in fermentation process in fermentation process
Temperature at 24 ~ 28 DEG C, control pressure in 0.04 ~ 0.06Mpa, control ventilation in 0.5 ~ 1.5VVM, control revolving speed 100 ~
250rpm, dissolved oxygen electrode on-line monitoring, to ensure dissolved oxygen in 30% or more (assuming that the initial dissolved oxygen of fermentor is 100%).
Ferment 48h, and PMV reaches 21%, starts from the feed supplement stream into fermentor of the flow velocity in every liter of fermentation liquid with 0.15ml/h
Add 15% 10- methylundecane acid ammonium solution, continuing fermentation stops fermentation, fermentation when fermentation unit no longer increases after 120h
Liquid tune PH to 11.5,50 DEG C of water-bath 1h, filtering, it is 1.49g/L that HPLC, which detects fermentation unit,.
Stream plus 10- methyl undecanoic acid potassium solution in 4 fermentation process of embodiment
700L seed culture medium is prepared in 1T seeding tank, 28 DEG C is cooled to after 120 DEG C of sterilizing 30min, by seed culture
The inoculum concentration of base volume ratio 0.3% accesses the shake-flask seed in 48h kind age, then 28 DEG C of culture 72h.
10000L fermentation medium is prepared in 20T fermentor, is cooled to 26 DEG C after 120 DEG C of sterilizing 30min, by fermentation training
The inoculum concentration for supporting base volume ratio 6% accesses trophosome inoculum in above-mentioned seed culture medium, controls in fermentation process in fermentation process
Temperature at 24 ~ 28 DEG C, control pressure in 0.04 ~ 0.06Mpa, control ventilation in 0.5 ~ 1.5VVM, control revolving speed 100 ~
250rpm, dissolved oxygen electrode on-line monitoring, to ensure dissolved oxygen in 30% or more (assuming that the initial dissolved oxygen of fermentor is 100%).
Ferment 48h, and PMV reaches 23%, starts from the feed supplement stream into fermentor of the flow velocity in every liter of fermentation liquid with 0.13ml/h
Add 15% 10- methyl undecanoic acid potassium solution, continuing fermentation stops fermentation, fermentation when fermentation unit no longer increases after 120h
Liquid tune PH to 11.5,50 DEG C of water-bath 1h, filtering, it is 1.39g/L that HPLC, which detects fermentation unit,.
The methyl oleate solution of stream plus 10- methyl undecanoic acid in 5 fermentation process of embodiment
300L seed culture medium is prepared in 500L seeding tank, is cooled to 28 DEG C after 120 DEG C of sterilizing 30min, is trained by seed
The shake-flask seed in the inoculum concentration access 48h kind age of base volume ratio 0.5% is supported, then 28 DEG C of culture 72h.
3500L fermentation medium is prepared in 5000L fermentor, is cooled to 26 DEG C after 120 DEG C of sterilizing 30min, by fermentation
Culture volume accesses trophosome inoculum in above-mentioned seed culture medium than 8% inoculum concentration, and control temperature is 24 in fermentation process
~ 28 DEG C, control pressure controls revolving speed in 100 ~ 250rpm, dissolved oxygen electricity in 0.5 ~ 1.5VVM in 0.04 ~ 0.06Mpa, control ventilation
Pole on-line monitoring, to ensure dissolved oxygen in 30% or more (assuming that the initial dissolved oxygen of fermentor is 100%).
Fermentation for 24 hours, PMV reaches 21%, start from the flow velocity in every liter of fermentation liquid with 0.03ml/h flow into fermentor add
The methyl oleate solution of 40% 10- methyl undecanoic acid, continuing fermentation stop hair after 120h when fermentation unit no longer increases
Ferment, fermentation liquid tune pH to 11.5,50 DEG C of water-bath 1h, filtering, it is 1.42g/L that HPLC, which detects fermentation unit,.
Claims (3)
1. a kind of method for producing Dalbavancin precursor A40926, which is characterized in that during the fermentation into fermentation medium
Add 10- methyl undecanoic acid or its salt: where
(1) after 24~48h of fermented and cultured, the flow velocity in every liter of fermentation liquid with 0.03~0.07ml/h is flowed into fermentor to be added
The methyl oleate solution of 10- methyl undecanoic acid, until fermentation ends；The oleic acid first for the 10- methyl undecanoic acid that the stream adds
The concentration of ester solution is 40%~60% (w/w)；Alternatively,
(2) after 24~48h of fermented and cultured, the flow velocity in every liter of fermentation liquid with 0.1~0.3ml/h is flowed into fermentor to be added
The aqueous solution of 10- methylundecane hydrochlorate, until the concentration of fermentation ends, the stream plus 10- methylundecane acid salt solution is 5
~15% (w/v), the 10- methylundecane hydrochlorate are 10- methyl undecanoic acid sodium, 10- methyl undecanoic acid potassium, 10- first
Base hendecanoic acid ammonium or its any two or three mixture；
Also, the strain used that ferments is the village Ye Ye actinomyces.
2. method according to claim 1, which is characterized in that after 24~48h of fermented and cultured, when biomass PMV reaches
Start stream plus 10- methyl undecanoic acid or its salt when 20% or more, until fermentation ends, wherein the biomass PMV is defined as:
Take 10ml fermentation liquid to be placed in graduated centrifuge tube 3000rpm and be centrifuged 15min, pouring out supernatant volume is V, then PMV=(10-V)/
10。
3. method according to claim 1, which is characterized in that fermentation temperature be 24~28 DEG C, pressure be 0.04~
0.06Mpa, ventilatory capacity are 0.5~1.5VVM, and revolving speed is 100~250rpm.
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| CN110551786B (en) * | 2019-09-12 | 2021-12-07 | 浙江海正药业股份有限公司 | Fermentation medium for increasing yield of A40926B 0 and method thereof |
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