CN104561198B - A kind of method of fermenting and producing feldamycin - Google Patents
A kind of method of fermenting and producing feldamycin Download PDFInfo
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- CN104561198B CN104561198B CN201310488580.9A CN201310488580A CN104561198B CN 104561198 B CN104561198 B CN 104561198B CN 201310488580 A CN201310488580 A CN 201310488580A CN 104561198 B CN104561198 B CN 104561198B
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Abstract
The invention discloses a kind of methods of fermenting and producing feldamycin.During fermenting and producing feldamycin, by way of adding edible oil into fermentation liquid, the yield of target product is improved, when fermentation liquid dissolved oxygen is by minimum point bottom out, starts batch-type or continuous type adds edible oil.This method makes easy to operate, and mild condition, raw material sources are extensive, and equipment requirement is low, reduces production cost, and substantially increase fermentation yield, is suitble to industrialized production.
Description
Technical field
The present invention relates to microbial fermentations to produce antibiotic technical field, and in particular to the fermenting and producing of feldamycin.
Background technique
Feldamycin (fidaxomicin) is that the macrolides for the novel narrow spectrum of one kind researched and developed by Optimer company resist
Raw element, trade name Dificid are mainly used for treating clostridium difficile associated diarrhea (CDAD), obtain on May 27th, 2011
FDA approval listing.With current main therapeutic agent metronidazole compared with vancomycin, feldamycin can significantly reduce recurrence
Rate.Feldamycin structural formula is as follows:
The preparation of feldamycin is mainly by actinomycete dactylosporangium aurantiacum (Dactylosporangium
Aurantiacum) fermented process generates.It is reported in terms of feldamycin zymotechnique both at home and abroad at present seldom.
The some processes of fermentation involved in CA1040564, GB1458512, US3978211 excessively simplify, and culture medium lacks effect carbon nitrogen late
Source, ferment effect are bad.The related carbon nitrogen source and microelement of fermentation are referred in United States Patent (USP) US20100028970, and are related to
And arrived and used the culture medium containing glucose, inorganic salts, amino acid and yeast extract in fermentation process, but above-mentioned fermentation side
Method still has trivial operations, the low problem of tunning yield, and the demand with world market to antibiotic not only increases, because
This needs to improve the effective improved method of feldamycin fermentation unit.
Summary of the invention
It is an object of the present invention to for deficiency existing for existing feldamycin zymotechnique, it is dynamic based on microorganism growth
Mechanical foundation provides a kind of liquid fermentation method that can be improved feldamycin yield, and its technical solution is as follows:
1) trophosome inoculum is cultivated in seed culture medium；
The seed culture medium preparation method:
Glucose 20g/L, soluble starch 30g/L, yeast extract 5g/L, peptone 5g/L, 2 g/L of magnesium sulfate, chlorine
Change sodium 2g/L, calcium carbonate 2g/L, PH7.0.
Suitable seed culture medium is prepared, 27-29 DEG C is cooled to after 120 DEG C of sterilizing 30min, by seed culture medium volume ratio
The inoculum concentration of 0.1-0.3% accesses the shake-flask seed in 48h kind age, then 27-29 DEG C of culture 28-36h.
2) fermentation accumulation feldamycin in the fermentation medium；
The fermentation medium preparation method:
Glucose 20g/L, soluble starch 50g/L, yeast powder 10g/L, peptone 5g/L, soybean powder 20g/L, magnesium sulfate
2 g/L, sodium chloride 2g/L, dipotassium hydrogen phosphate 1g/L, calcium carbonate 2g/L, PH7.0.
Suitable fermentation medium is prepared, 27-29 DEG C is cooled to after 120 DEG C of sterilizing 30min, by fermentation medium volume ratio
Trophosome inoculum in the inoculum concentration access step 1) seed culture medium of 4-8%, in fermentation process control temperature at 27-29 DEG C,
Pressure is controlled in 0.04-0.06Mpa, control ventilation controls revolving speed in 100-250rpm, dissolved oxygen electrode is online in 0.5-1.5VVM
Monitoring, to ensure dissolved oxygen in 30% or more (assuming that the initial dissolved oxygen of fermentor is 100%).
Fermented and cultured is continued to carry out, dissolved oxygen amount reduces as far as possible in 48-72h indirect fermentation tank, when fermentation liquid dissolved oxygen is by most
Start to add edible oil when low spot bottom out, and continuing fermentation stops addition edible oil after the 160h that ferments, fermentation 180h it
Afterwards, stop fermentation when potency no longer increases, obtain product.
The addition edible oil is selected from soybean oil, corn oil, rapeseed oil, sesame oil, olive oil, peanut oil or sunflower seeds
Oil or in which several arbitrary combinations.
The preparation of the edible oil: edible oil is poured into feed supplement tank, 120 DEG C of sterilizing 30min, for use.
The edible oil addition, with 24 hours for a chronomere, each chronomere's addition and fermentating liquid volume
Than the edible oil for 0.5%-1.2%, addition manner is continuous type or discontinuous form.
Preferably, the amount of each chronomere's addition edible oil is the 1.0% of fermentating liquid volume.
The continuous type addition, controls additive amount, continual that edible oil is added into fermentor.
The discontinuous form addition, each chronomere adds edible oil 2-4 times.
Preferably, discontinuous form adds, and adds an edible oil for every eight hours, and a chronomere adds 3 times, adds every time
For the edible oil of the 0.2%-0.4% of fermentating liquid volume ratio, more preferably 0.3%.
In the present invention, the bacterial strain used that ferments is dactylosporangium aurantiacum (Dactylosporangium aurantiacum),
The strain can be obtained by following mechanisms: Chinese agriculture Microbiological Culture Collection administrative center (Agricultural Culture
Collection of China), bacterial strain deposit number: ACCC40816.
Further, above-mentioned fermentation liquid is isolated and purified, obtains the feldamycin of high-purity.
Of the invention is easy to operate, and mild condition, raw material sources are extensive, and equipment requirement is low, reduces production cost, and
And fermentation yield is substantially increased, more suitable for industrialized production.Especially applicant is found surprisingly that, by adding edible oil
Mode, not only ensure that sufficient carbon source, it is also continual supplemented with the conjunction of feldamycin biology by the utilization of microorganism
At substances such as synthesis precursor propionyl coenzyme As important in approach, to substantially increase the yield of target product.Further
, applicant further found that, during the fermentation, since fermentor dissolved oxygen amount reduce as far as possible and when bottom out add food
With oil, and with 24 hours for a chronomere, each chronomere's addition and fermentating liquid volume are than the food for 0.5%-1.2%
It is added with the mode of oil, ensure that the supply of important synthesis precursor substance, meet the needs of microbial fermentation, greatly increase training
Base utilization rate is supported, fermentation level significantly improves, and 50% or more fermentation yield can be improved compared with current technique, and it is suitable for works
Industry metaplasia produces.
Detailed description of the invention
The HPLC chromatogram of feldamycin detection in the fermentation liquid of edible oil is added in Fig. 1 embodiment 1.
The HPLC chromatogram that feldamycin detects in the fermentation liquid of edible oil is not added in Fig. 2 embodiment 8.
Fig. 3 embodiment 9 by separation of fermentative broth in embodiment 1 after purification feldamycin detection HPLC chromatogram.
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.By dactylosporangium aurantiacum (Dactylosporangium aurantiacum)
ACCC40816-80 DEG C of refrigerator freezing processes save.Shaking flask culture: the seed culture medium of preparation 1L in 2.5L seeding tank, 120 DEG C
27 DEG C are cooled to after sterilizing 30min, accesses ACCC40816 strain, the shaking flask culture under 30 DEG C, revolving speed 200rpm.
Batch-type adds edible oil in 1 fermentation process of embodiment
300L seed culture medium is prepared in 500L seeding tank, is cooled to 27 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 0.1% is supported, then 27 DEG C of culture 28h.
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 4% inoculum concentration, controlled at 27 in fermentation process
DEG C, control pressure is 0.04Mpa, and control ventilation is 0.5VVM, and control revolving speed is 100rpm, to ensure dissolved oxygen 30% or more.
Fermented and cultured is continued to carry out, dissolved oxygen amount is down to 32% in 48h post-fermentation tank, and gradually bottom out, with 8 hours/
It is secondary, soybean oil is added into fermentor, the dosage for adding soybean oil every time is the 0.2% of fermentating liquid volume, and continuing fermentation, hair
Soybean oil is added in stopping after ferment 160h, after the 180h that ferments, stops fermenting when potency no longer increases, acquisition product, under 228nm,
Ultrasonic 30min, HPLC detection, chromatogram is as shown in Figure 1, fermentation unit is 3.18 g/L in fermentation liquid.
Continuous type adds edible oil in 2 fermentation process of embodiment
100L seed culture medium is prepared in 200L seeding tank, 27-29 DEG C is cooled to after 120 DEG C of sterilizing 30min, by seed
Inoculum concentration of the culture volume than 0.3% accesses the shake-flask seed in 48h kind age, then 29 DEG C of culture 36h.
1400L fermentation medium is prepared in 2000L fermentor, is cooled to 29 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, controlled at 29 in fermentation process
DEG C, control pressure is 0.06Mpa, and control ventilation is 1.5VVM, and control revolving speed is 250rpm, to ensure dissolved oxygen 30% or more.
Fermented and cultured is continued to carry out, dissolved oxygen amount was down to 33% in 64h post-fermentation tank, and gradually bottom out, with 24 hours
It is continual with the flow velocity of 48ml/min between 64 hours to 88 hours (first chronomere) for a chronomere
Corn oil is added into fermentor, keeps that each chronomere adds and fermentating liquid volume is than the corn oil for 0.5%, and is held
Supervention ferment, ferment 160h after stop addition corn oil, ferment 180h after, when potency no longer increases stop fermentation, acquisition product,
Under 228nm, ultrasonic 30min, HPLC are detected, and fermentation unit is 2.97g/L in fermentation liquid.
Batch-type adds edible oil in 3 fermentation process of embodiment
100L seed culture medium is prepared in 200L 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 0.2% is supported, then 28 DEG C of culture 30h.
700L fermentation medium is prepared in 1000L fermentor, is cooled to 28 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, and control temperature is 28 in fermentation process
DEG C, for control pressure in 0.05Mpa, control ventilation controls revolving speed in 200rpm, to ensure dissolved oxygen 30% or more in 1.0VVM.
Fermented and cultured is continued to carry out, dissolved oxygen amount is down to 30% in 52h post-fermentation tank, and gradually bottom out, with 8 hours/
It is secondary, rapeseed oil is added into fermentor, the dosage for adding rapeseed oil every time is the 0.3% of fermentating liquid volume, and continuing fermentation, hair
Rapeseed oil is added in stopping after ferment 160h, after the 180h that ferments, stops fermenting when potency no longer increases, acquisition product, under 228nm,
Ultrasonic 30min, HPLC are detected, and fermentation unit is 3.37g/L in fermentation liquid.
Continuous type adds edible oil in 4 fermentation process of embodiment
250L 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 0.2% is supported, then 28 DEG C of culture 32h.
1200L fermentation medium is prepared in 2000L fermentor, is cooled to 29 DEG C after 120 DEG C of sterilizing 30min, by fermentation
Culture volume accesses trophosome inoculum in above-mentioned seed culture medium than 6% inoculum concentration, controlled at 28 in fermentation process
DEG C, control pressure is 0.05Mpa, and control ventilation is 1.2VVM, and control revolving speed is 200rpm, to ensure dissolved oxygen 30% or more.
Fermented and cultured is continued to carry out, dissolved oxygen amount was down to 35% in 62h post-fermentation tank, and gradually bottom out, with 24 hours
It is continual with the flow velocity of 66ml/min between 62 hours to 86 hours (first chronomere) for a chronomere
Sesame oil is added into fermentor, keeps that each chronomere adds and fermentating liquid volume is than the sesame oil for 0.8%, and is held
Supervention ferment, ferment 160h after stop addition sesame oil, ferment 180h after, when potency no longer increases stop fermentation, acquisition product,
Under 228nm, ultrasonic 30min, HPLC are detected, and fermentation unit is 3.28 g/L in fermentation liquid.
Batch-type adds edible oil in 5 fermentation process of embodiment
100L seed culture medium is prepared in 200L 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 0.2% is supported, then 27 DEG C of culture 34h.
500L fermentation medium is prepared in 1000L fermentor, is cooled to 28 DEG C after 120 DEG C of sterilizing 30min, by fermentation training
The inoculum concentration for supporting base volume ratio 4% accesses trophosome inoculum in above-mentioned seed culture medium, and control temperature is 28 in fermentation process
DEG C, for control pressure in 0.05Mpa, control ventilation controls revolving speed in 200rpm, to ensure dissolved oxygen 30% or more in 1.0VVM.
Fermented and cultured is continued to carry out, dissolved oxygen amount is down to 31% in 72h post-fermentation tank, and gradually bottom out, with 8 hours/
It is secondary, olive oil is added into fermentor, the dosage for adding olive oil every time is the 0.4% of fermentating liquid volume, and continuing fermentation, hair
Olive oil is added in stopping after ferment 160h, after the 180h that ferments, stops fermenting when potency no longer increases, acquisition product, under 228nm,
Ultrasonic 30min, HPLC are detected, and fermentation unit is 3.25g/L in fermentation liquid.
Continuous type adds edible oil in 6 fermentation process of embodiment
250L 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 0.3% is supported, then 28 DEG C of culture 32h.
600L fermentation medium is prepared in 1500L fermentor, is cooled to 29 DEG C after 120 DEG C of sterilizing 30min, by fermentation training
The inoculum concentration for supporting base volume ratio 4% accesses trophosome inoculum in above-mentioned seed culture medium, controlled at 28 in fermentation process
DEG C, control pressure is 0.05Mpa, and control ventilation is 1.2VVM, and control revolving speed is 200rpm, to ensure dissolved oxygen 30% or more.
Fermented and cultured is continued to carry out, dissolved oxygen amount was down to 33% in 70h post-fermentation tank, and gradually bottom out, with 24 hours
It is continual with the flow velocity of 50ml/min between 70 hours to 94 hours (first chronomere) for a chronomere
Freshen peanut oil into fermentor and miscella that sunflower oil adds volume ratio 1:1 to mix, keep each chronomere add and
Fermentating liquid volume is than the miscella for 1.2%, and continuing fermentation, stops addition miscella after the 160h that ferments, after the 180h that ferments,
Stopping is fermented when potency no longer increases, acquisition product, and under 228nm, ultrasonic 30min, HPLC are detected, and fermentation unit is in fermentation liquid
3.17 g/L。
Batch-type adds edible oil in 7 fermentation process of embodiment
300L seed culture medium is prepared in 500L seeding tank, is cooled to 27 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 0.1% is supported, then 27 DEG C of culture 28h.
3000L 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 5% inoculum concentration, controlled at 27 in fermentation process
DEG C, control pressure is 0.04Mpa, and control ventilation is 0.5VVM, and control revolving speed is 100rpm, to ensure dissolved oxygen 30% or more.
Fermented and cultured is continued to carry out, dissolved oxygen amount is down to 33% in 52h post-fermentation tank, and gradually bottom out, with 8 hours/
Secondary, soybean oil is added into fermentor: rapeseed oil: sesame oil is the miscella of 1:1:1, and the dosage for adding miscella every time is hair
The 0.2% of zymotic fluid volume, and continuing fermentation, ferment 160h after stop addition miscella, ferment 180h after, potency no longer increases
When stop fermentation, obtain product, under 228nm, ultrasonic 30min, HPLC detection, fermentation unit is 2.93g/L in fermentation liquid.
Edible oil is not added in 8 fermentation process of embodiment
300L seed culture medium is prepared in 500L seeding tank, is cooled to 27 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 0.1% is supported, then 28 DEG C of culture 28h.
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 4% inoculum concentration, controlled at 27 in fermentation process
DEG C, control pressure is 0.04Mpa, and control ventilation is 0.5VVM, and control revolving speed is 100rpm, to ensure dissolved oxygen 30% or more.
Fermented and cultured is continued to carry out, after the 180h that ferments, stops fermentation when potency no longer increases, obtains product, 228nm
Under, ultrasonic 30min, HPLC detection, chromatogram is as shown in Fig. 2, fermentation unit is 1.67g/L in fermentation liquid.
Embodiment 9 isolates and purifies the fermentation liquid in embodiment 1 and obtains feldamycin
Fermentation liquid 80L in Example 1, filters pressing obtain 28.5kg mycelium.It is added 90L's 70% into mycelium
Ethanol solution stirs 5 hours, filtrate 94.3L is obtained by filtration, and includes feldamycin 187g through HPLC detection filtrate.By filtrate
With purified water be diluted to concentration of alcohol be 50% after, import SP825L adsorb resin, loading amount 20L, the second of resin 40L 60%
Alcoholic solution prewashing, flow velocity (1BV/h) are then desorbed with the ethanol solution of 100L 70%, flow velocity (1BV/h), and every 2L collects one
Component, and purity is mixed in 70% or more component.Then mixed composition is concentrated under reduced pressure into concentration of alcohol is 13%.It stands cold
But it to 15 DEG C, filters, is dried to obtain 224g yellow solid, yield 71.8%, HPLC:76.7%.
Above-mentioned 224g yellow solid is dissolved in 3.5L ethyl acetate, dissolves, 5 DEG C is cooled to, under stiring by 2.3L
5 DEG C of petroleum ether instills in above-mentioned ethyl acetate solution, maintains temperature to stir 5 hours at 3-8 DEG C after dripping.Filtering, will
Filter cake vacuum drying, obtains off-white powder 192g, yield 85%, HPLC:77.3%.
Above-mentioned off-white powder 40g is dissolved into upper prop liquid with 50% acetonitrile solution of 1L, imports 40 resin of UniPS
It is adsorbed, resin loading amount is 5L, and upper column flow rate is 5L/h.Then it is desorbed with the acetonitrile solution of 40L 65%, point
Section is collected, and 95% or more component of purity is mixed.Mixed liquor is concentrated in vacuo to after solid is precipitated at a temperature of 50-60 DEG C and has been stopped
It is only concentrated, is cooled to room temperature, ethyl acetate stirring is added, dissolves, extraction discards water layer.Combined ethyl acetate layer is concentrated to dryness,
White solid is obtained, ethyl alcohol is added and is heated to 50 DEG C of dissolutions, ethanol consumption is 12 times of white solid weight, is dropped under stiring
Temperature has white solid precipitation to 5 DEG C, continues stirring and is not further added by solid is precipitated, and filters, and vacuum drying obtains white powder
21.3g, total recovery 53.3%, HPLC:99.1%(HPLC chromatogram is as shown in attached drawing 3).
The feldamycin that Analyze & separate goes out, obtains following data:
Mp 129-140 DEG C (white powder obtained by RP-HPLC)；
MS m/z (ESI)1079.7 (M+Na)+；
1H NMR (400 MHZ,CD3OD) δ 7.21(d, 1H), 6.58 (dd, 1H), 5.95 (ddd, 1H), 5.85(br s,
1H), 5.57(t, 1H), 5.12 (br d, 1H), 5.08(t, 1H), 5.01(d, 1H) and, 4.70(m, 1H) 4.71(br s, 1H),
4.62(br s, 1H), 4.63(d, 1H), 4.41(d, 1H) and, 4.22(m, 1H), 4.01(pentet, 1H) and, 3.91
(dd,1H),
3.75 (m, 2H), 3.71 (d, 1H), 3.55(s, 3H), 3.52-3.55 (m, 2H), 2.90 (m, 2H), 2.65-2.75
(m, 3H),
2.59 (heptet, 1H), 2.48(ddd, 1H), 2.43(ddd, 1H), 2.02 (dq, 1H), 1.81(s, 3H) and, 1.76
(s, 3H), 1.65 (s, 3H), 1.35 (d, 3H), 1.29(m, 1H), 1.21(t, 3H), 1.17 (d, 3H), 1.15 (d, 3H),
1.16 (d, 3H), 1.14 (s, 3H), 1.12 (s, 3H), 0.87 (t, 3H).
Embodiment 10 isolates and purifies the fermentation liquid in embodiment 2 and obtains feldamycin
Fermentation liquid 80L in Example 2 finally obtains feldamycin by similarly isolating and purifying in such as embodiment 8
White powder 22.03g, yield 54.1%, purity 98.88%.
Embodiment 11 isolates and purifies the fermentation liquid in embodiment 3 and obtains feldamycin
Fermentation liquid 80L in Example 3 finally obtains feldamycin by similarly isolating and purifying in such as embodiment 8
White powder 19.3g, total recovery 50.6%, HPLC:98.7%.
Embodiment 12 isolates and purifies the fermentation liquid in embodiment 4 and obtains feldamycin
Fermentation liquid 80L in Example 4 finally obtains feldamycin by similarly isolating and purifying in such as embodiment 8
White powder 25.7g, total recovery 53%, HPLC:98.9%.
Claims (4)
1. a kind of method of fermenting and producing feldamycin, the fermentation process include:
1) trophosome inoculum is cultivated in seed culture medium；
2) trophosome inoculum is accessed in the fermentation medium, and adds edible oil, and continuing fermentation obtains feldamycin, feature
It is, fermentation dissolved oxygen amount into 48-72h indirect fermentation liquid reduces as far as possible, when fermentation liquid dissolved oxygen when minimum point bottom out by opening
Begin addition edible oil, stops addition edible oil after fermentation 160 hours, the addition of the edible oil is with 24 hours for a time list
Position, each chronomere's addition and fermentating liquid volume are than the edible oil for 0.5%-1.2%, and addition manner is continuous type, control
Additive amount, uninterrupted addition；Or addition manner is discontinuous form, each chronomere adds edible oil 2-4 times, and sends out
The bacterial strain that ferment uses is dactylosporangium aurantiacum；The edible oil be selected from soybean oil, corn oil, rapeseed oil, sesame oil, olive oil,
Peanut oil or sunflower oil or in which several arbitrary combinations.
2. the method as described in claim 1, which is characterized in that the addition manner of edible oil is batch-type, adds 1 for every eight hours
Secondary edible oil, a chronomere adds 3 times, is added to the edible oil of the 0.2-0.4% of fermentating liquid volume ratio every time.
3. the method as described in claim 1, it is characterised in that press the inoculum concentration of fermentation medium volume ratio 4-8% in step 2)
Access the trophosome inoculum in step 1) seed culture medium.
4. the method as described in claim 1, it is characterised in that fermentation condition temperature is 27-29 DEG C in step 2), and pressure is
0.04-0.06Mpa ventilates as 0.5-1.5VVM, revolving speed 100-250rpm.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1688707A (en) * | 2002-07-29 | 2005-10-26 | 浩鼎生技公司 | Tiacumicin production |
| CN103275152A (en) * | 2013-05-29 | 2013-09-04 | 华北制药集团新药研究开发有限责任公司 | Preparation method of high-purity fidaxomicin |
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2013
- 2013-10-18 CN CN201310488580.9A patent/CN104561198B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1688707A (en) * | 2002-07-29 | 2005-10-26 | 浩鼎生技公司 | Tiacumicin production |
| CN103275152A (en) * | 2013-05-29 | 2013-09-04 | 华北制药集团新药研究开发有限责任公司 | Preparation method of high-purity fidaxomicin |
Non-Patent Citations (1)
| Title |
|---|
| Tiacumicins, a novel complex of 18-membered macrolide antibiotics. I. Taxonomy, fermentation and antibacterial activity;ROBERT J. THERIAULT等;《THE JOURNAL OF ANTIBIOTICS》;pubmed;19861107;第40卷(第5期);第567页，第568页第2-4段发酵部分 |
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