CN103087928B - Fungus Glarea lozoyensis and application thereof for controlling microbial metabolite Pneumocandin Kangding B0 - Google Patents
Fungus Glarea lozoyensis and application thereof for controlling microbial metabolite Pneumocandin Kangding B0 Download PDFInfo
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- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
The invention discloses a fungus (Glarea lozoyensis) FIM 2006071. The strain is preserved in China Center for Type Culture Collection, the preservation number of the strain is CCTCC NO: M2012475, and the preservation date is 23rd, November, 2012. The invention further discloses a high-unit intermediate Pneumocandin Kangding B0 of caspofungin, which is obtained through controlling microbial metabolite. The fermentaition strain provided by the invention is good in performance, stable in production ability, high in fermentation unit and generates relatively less fermentation by-products, so that post-extraction difficulty is reduced, high-quality caspofungin is obtained favorably, and therefore, the strain is suitable for industrial mass production.
Description
Technical field
The present invention relates to a kind of novel microorganism and application thereof, relate in particular to a kind of fungus G larea lozoyensis and obtain not Kangding B of knob by regulating microorganism metabolism
0application.
Background technology
Echinocandin claims again echinocandin, it is the novel antifungal drug of a class, belong to acetyl six lopps, toxicity to human body is low, be a kind of water miscible lipopeptid, be mainly used in treating candidiasis esophagitis or oropharynx inflammation, invasive aspergillosis and other antifungal drugs are failed to respond to any medical treatment or can not resistance to receptor, Ka Shi lung spore bacterium is also had to effect, the performance antifungic action by the synthetic of Antifungi cell walls important composition composition β (1,3)-D-Glucose.Caspofungin (Caspofungin) is the echinocandin antifungal agent of first approval listing.For treatment persistent fever and the less patient of neutrophil leucocyte, Caspofungin is as empirical treatment, its security, survival rate and efficient all higher, and tolerance is better, treatment fungi infestation and candidemia are also effective, can kill the Aspergillus fumigatus cell of growing.
Caspofungin is by not Kangding B of knob
0(Pneumocandin B
0) after structural modification, obtain.Wherein not Kangding B of knob
0be the microbial metabolites of fungi (Glarea lozoyensis), can, by regulating and controlling the also i.e. fermentation generation of microbial metabolism of fungies (Glarea lozoyensis), after extracting purifying, synthesize and obtain Caspofungin through polystep reaction again.General knob is Kangding B not
0produce bacterium, throughput is unstable, and output is lower, fermentation byproduct is more, and impurity is also more, causes rear extraction process comparatively complicated, increase widely follow-up purification difficulty, and be difficult to obtain highly purified final product, thereby be difficult to carry out better industrialization production.
Summary of the invention
The object of the invention is for the problems referred to above, provide a kind of fermentation unit high, can stably manufactured, output is high and by product is few not Kangding B of knob
0produce bacterium.
Another object of the present invention is to provide this bacterial strain and is preparing not Kangding B of knob
0in application, and concrete fermentation preparation.
The object of the invention is to realize by following technical proposal:
A kind of fungi FIM2006071, Classification And Nomenclature is Glarea lozoyensis FIM2006071, by Chinese Typical Representative culture collection center preservation (being called for short CCTCC), preserving number is: CCTCC NO:M2012475, preservation date is: on November 23rd, 2012.
Described preserving number is that the bacterial strain of CCTCC NO:M2012475 obtains from the screening of Foochow, Fujian Province.
Described preserving number is the colony characteristics of the bacterial strain of CCTCC NO:M2012475: bacterium colony subcircular, and edge white, irregular fan-shaped, colony diameter 7.5-17.8mm, bacterium colony protuberance, in be formed centrally knot or subside into hole, middlely produce without secretory product and soluble pigment.
According to the description of microbial morphology and external related data, be the various cultural characteristics of the bacterial strain of CCTCC NO:M2012475 in conjunction with preserving number, this preserving number is that the bacterial strain of CCTCC NO:M2012475 belongs to fungi, names the FIM2006071 into Glarea lozoyensis.
Described preserving number is that the bacterial strain of CCTCC NO:M2012475 can be applicable to fermentation and prepares not Kangding B of knob
0.This preparation method comprises the following steps:
A. bacterial strain employing deposit number is the bacterial strain of CCTCC NO:M2012475;
B. the inoculum size access shake-flask seed substratum of 30% glycerine mycelia freeze pipe of preparation according to a conventional method being pressed to the 3-5% of shake-flask seed culture volume, 220-260rpm, cultivates 2-3 days, obtains shake-flask seed liquid; Shake-flask seed liquid is inoculated in to seeding tank by the inoculum size of the long-pending 0.1-0.2% of seed tank culture matrix, and 120-200 rpm, cultivates 3-4 days, obtains tank seed liquor; Tank seed liquor is inoculated in to fermentation tank culture medium by the inoculum size of the 5-15% of fermentation volume, 150-200 rpm, fermentation culture 9-12 days, collects fermented liquid; Wherein culture temperature is 22-26 DEG C.
The ratio of the wherein said each component of shake-flask seed substratum in substratum is: in every 100mL substratum, and carbon source 1-8g, nitrogenous source 2-8g, inorganic salt 0-2.5g, all the other are water;
The ratio of the each component of seed tank culture base in substratum is: in every 100mL substratum, and carbon source 2-8g, nitrogenous source 1-7g, inorganic salt 0-2.5g, all the other are water;
The ratio of the each component of fermention medium in substratum is: in every 100mL substratum, and carbon source 8-16g, nitrogenous source 1-5g, inorganic salt 0-1g, amino acid 0-2g, all the other are water.
The each component of wherein said substratum ratio in substratum, is preferably:
The ratio of the each component of shake-flask seed substratum is: in every 100mL substratum, and carbon source 2-4g, nitrogenous source 4-6g, inorganic salt 1-2g, all the other are water;
The ratio of the each component of seed tank culture base is: in every 100mL substratum, and carbon source 4-6g, nitrogenous source 3-5g, inorganic salt 0.5-1.5g, all the other are water;
The ratio of the each component of fermention medium is: in every 100mL substratum, and carbon source 10-14g, nitrogenous source 2-4g, inorganic salt 0.3-0.5g, amino acid 0.5-1.5g, all the other are water.
Wherein said carbon source is selected from potato starch, W-Gum, Zulkovsky starch, maltodextrin, potato dextrin, and glycerine, glucose, maltose, murphy juice, potato leach one or more in powder, N.F,USP MANNITOL; Described nitrogenous source is selected from one or more in soybean cake powder, raw bean powder, dregs of beans, corn steep liquor, corn starch, silkworm chrysalis hydrolyzed solution, urea, ammonium sulfate, yeast powder, yeast extract powder, cottonseed meal, dried silkworm chrysalis meal; Inorganic salt are K
2hPO
4, MnSO
44H
2o, NaCl, Fe (NH
4)
2(SO
4)
26H
2o, NaNO
3, KNO
3, MgSO
47H
2o, FeSO
47H
2o, KH
2pO
4in one or more; Amino acid is one or more in 1B, L-Leu, ILE, TYR, L-threonine, Serine, L-PROLINE, L-arginine.
Wherein said medium optimization is: carbon source is one or more in glucose, N.F,USP MANNITOL; Nitrogenous source is one or more in yeast extract powder, corn starch, yeast powder, cottonseed meal, raw bean powder; Inorganic salt are KH
2pO
4, K
2hPO
4, MnSO
44H
2o, FeSO
47H
2one or more in O; Amino acid is one or more in L-PROLINE, L-threonine.
Preserving number of the present invention is that the bacterial strain of CCTCC NO:M2012475 is the not Kangding B of knob of a kind of natural high unit of being separated at present
0generation bacterium, leavening property is good, can be used for scale operation.Fermenting process is not Kangding B of knob
0the important step of producing, its fermentation level is directly related with technique quality, tests its stable production capacity in zymotechnique process shaking flask provided by the invention and 10 tons of fermentor tanks.After testing, not Kangding B of the knob of preparing with bacterial classification provided by the invention and fermentation culture method
0fermentation unit can up to 3000 about μ g/mL or more than, thereby provide good basis for follow-up suitability for industrialized production.Simultaneously fermentation byproduct of the present invention is relatively less, and has reduced the difficulty of rear extraction, thereby is conducive to the acquisition of the Caspofungin of high-quality, has advantage being applied in suitability for industrialized production.
Bacterial strain preservation situation: be preserved in Chinese Typical Representative culture collection center, Wuhan (being called for short CCTCC), deposit number is CCTCC NO:M2012475, and Classification And Nomenclature is fungi FIM2006071(Glarea lozoyensis FIM2006071).Preservation date is on November 23rd, 2012.
Embodiment
Be that the present invention conducts further description below in conjunction with specific embodiment, but method related in scheme and technical parameter can not be interpreted as to limitation of the present invention.
Embodiment 1: preserving number is cultivation and physiological and biochemical property and the utilization of carbon source situation of the bacterial strain of CCTCC NO:M2012475
1, preserving number is the morphological feature of the strain culturing of CCTCC NO:M2012475
By preserving number be the inoculation of CCTCC NO:M2012475 in yeast malt extract nutrient agar (YME), potato glucose agar medium (PDA), sabouraud's agar (SMA) etc. for observing the substratum of morphological specificity, cultivate 3 weeks, observe and be described for 23 DEG C.
Bacterium colony is 23 DEG C of cultivations on YME nutrient agar, growth limitation, 3 weeks diameter 11.7-15.4mm; Bacterium colony subcircular, edge is irregular fan-shaped; Bacterium colony protuberance, in be formed centrally knot or subside into hole; The velvet-like double rope form of quality; Bacterium colony surface forms radioactive wrinkle; Mycelia color bois de rose is extremely rose pink, the light brown of reverse side; Produce without secretory product and soluble pigment.
Bacterium colony is 23 DEG C of cultivations on PDA substratum, and bacterium colony circular edge is slightly irregular, and the thicker central elevation of bacterium colony has irregular radioactivity wrinkle; Colony growth is slower, 3 weeks diameter 7.5-17.8mm, the velvet-like double rope form of quality.Bacterium colony yellow-white the most at the beginning, white powder, forms dark bacterium colony along with cell age increases, and it is filbert that center is, adularescent edge; Reverse side color yellow-white at the beginning, extends Vandyke brown with incubation time.Produce without secretory product and soluble pigment.
Bacterium colony cultural characteristic on SMA substratum is similar on PDA substratum.Growth limitation, 3 weeks diameter 11.2-15mm; Bacterium colony subcircular, edge is irregular; Bacterium colony protuberance, in be formed centrally knot; The velvet-like double rope form of quality; Bacterium colony surface forms radioactive wrinkle; The light pink of mycelia is to white powder, reverse side color yellow-white; Produce without secretory product and soluble pigment.
2, preserving number is the bacterial strain Physiology and biochemistry cultural characteristic of CCTCC NO:M2012475
Bacterial strain FIM2006071 can not degraded cellulose.Six kinds of two pH cultural characteristics of substratum are listed in table 1.
Six kinds of medium pHs 4 of table 1 and pH7 cultural characteristic
| Substratum | Growing state | Base silk | Gas silk | Soluble pigment |
| Bell potato agar glucose pH4 | +++ | Lead | Light grey | Olive brown |
| Bell potato agar glucose pH7 | +++ | Tawny | Pale pinkish grey | Olive brown |
| Yeast malt extract nutrient agar pH4 | +++ | Light yellow | White powder | — |
| Yeast malt extract nutrient agar pH7 | +++ | Light yellow | White powder | — |
| Sabouraud's agar pH4 | +++ | Light yellow | White powder | — |
| Sabouraud's agar pH7 | +++ | Tawny | White powder | — |
| Czapek agar medium pH4 | ++ | Light tan | — | — |
| Czapek agar medium pH7 | + | White | — | — |
| Glucose czapek agar medium pH4 | + | Light tan | — | — |
| Glucose czapek agar medium pH7 | + | White | — | — |
| Glycerine czapek agar medium pH4 | + | White | — | — |
| Glycerine czapek agar medium pH7 | + | White | — | — |
+: growth is general; ++: grow medium; +++: growth is abundant;-: lack.
Soak (10% soil soaks juice, V/V) on juice nutrient agar at soil, 23 DEG C of cultivations start to form conidium in 2-3 week.Mycelia has tabula, diameter 2.5-3.5 μ m.Conidium budding type, directly breaks up generation by mycelia, without conidiophore; Conidium group's size, shape differ and form the structure of chain, bunch shape or bulk; Conidium is spherical, subsphaeroidal, diameter 5.0-14.4 μ m × 4.8-12 μ m.
3, utilization of carbon source
This time test is taking PDA substratum as basic medium, and 26 DEG C of cultivations, observed at the 3rd, 7,10 days respectively.Result is as shown in table 2 below, and test-results shows, this bacterial strain can assimilate D-semi-lactosi, sweet and pure, pectinose, N.F,USP MANNITOL, inositol, rhamnosyl, sweet dew alcohol and glucose.
The utilization of carbon source ability of table 2 fungi CCTCC NO:M2012475
| Carbon source | 3 days | 7 days | 10 days |
| Blank | ﹣ | ﹣ | ﹣ |
| D-semi-lactosi | ﹢﹣ | ﹢ | ﹢ |
| Sweet and pure | ﹢ | ﹢ | ﹢ |
| Pectinose | ﹢﹣ | ﹢ | ﹢ |
| Sucrose | ﹣ | ﹣ | ﹣ |
| Sorbyl alcohol | ﹣ | ﹣ | ﹣ |
| N.F,USP MANNITOL | ﹢﹣ | ﹢ | ﹢﹢ |
| Inositol | ﹢﹣ | ﹢ | ﹢ |
| Rhamnosyl | ﹢ | ﹢ | ﹢ |
| D-wood sugar | ﹣ | ﹣ | ﹣ |
| Raffinose | ﹣ | ﹢﹣ | ﹢﹣ |
| Seminose | ﹣ | ﹢ | ﹢ |
| Glucose | ﹢ | ﹢ | ﹢﹢ |
+: growth is general; ++: grow medium;-: not long
In conjunction with morphological feature and physiological and biochemical property and the utilization of carbon source situation analysis of bacterial strain, identify that isolated strains FIM2006071 is Glarea lozoyensis.
Embodiment 2: fermentation culture is prepared not Kangding B of knob
0
Adopting preserving number is the bacterial strain of CCTCC NO:M2012475.
1, seed spawn culture and preservation
Solid medium: glucose 4g, yeast extract powder 0.5g, KH
2pO
41g, soy peptone 0.5g, corn starch 1.5g, agar 2g, the 100mL that adds water, pH adjusts 7.0.
Solid culture method: inoculation, in culture medium slant, is cultivated 10-12 days for 26 DEG C.
After solid culture finishes, it is for subsequent use that 4-10 DEG C of refrigeration is placed on inclined-plane.
2, shake-flask seed is cultivated
Substratum: glucose 4g, yeast extract powder 2.5g, corn steep liquor 1.5g, raw bean powder 2g, KH
2pO
41g, the 100mL that adds water, pH adjusts 7.0.
Liquid amount: fill 100mL substratum in 500 mL triangular flasks
Inoculum size: 5%(V/V) 30% glycerine mycelia freeze pipe
Culture temperature: 26 DEG C
Incubation time: 3 days
Shaking speed: 260rpm
Shake-flask seed cultural method: after 30% glycerine mycelia freeze pipe is thawed according to inoculum size 5%(V/V) connect in shake-flask seed substratum, treat that mycelia grows, it is more than 25% having obvious wall cling phenomenon and bacterium dense, by 1L shake-flask seed nutrient solution, in access 1000L seeding tank.
The making of 30% glycerine mycelia freeze pipe: under sterile state, about the glycerine after sterilizing 30mL is added in the kind bottle of having grown, shake up and make 30% glycerine mycelia suspension, then divide and be filled to (5mL/ props up) in small test tube, place-20 DEG C of refrigerations for subsequent use.
3, seeding tank seed culture medium
Substratum: glucose 30kg, raw bean powder 5kg, yeast powder 10kg, cottonseed meal 5kg, corn steep liquor 5kg, KH
2pO
45kg, NaCl 2.5kg, the 500L that adds water, pH adjusts 7.0.
Loading amount: the in-built substratum 500L of 1000L seeding tank, 121 DEG C of sterilizing 30min.
Seed tank culture method: in cultured 1L shake-flask seed liquid access seeding tank, 26 DEG C, 4 days.In culturing process, control tank pressure: 0.04MPa, stirring velocity 120rpm, air flow 1:1(V/V).
After cultivation, microscopy mycelia is sturdy, and dyeing is dark, and without microbiological contamination, bacterium is dense >=and 15%
4, fermentor cultivation
Substratum: N.F,USP MANNITOL 400kg, W-Gum 100kg, cottonseed meal 100kg, yeast powder 50kg, raw bean powder 50kg, KH
2pO
45kg, FeSO
47H
2o 10kg, L-PROLINE 50kg, L-threonine 25kg, bubble enemy 7.5kg, adds water to 5000L, pH 7.0.
Loading amount: 5 tons of 10 tons of in-built substratum of fermentor tank
Fermentor cultivation method: on cultured 500L tank, seed liquor accesses in fermentor tank, 26 DEG C, 12 days.In culturing process, control tank pressure: 0.04MPa, stirring velocity 160rpm, air flow 1:1.3(V/V).
Fermentation termination judgement: mycelia dyeing is dark, and cavity is more, and mycelia has fracture, autolysis.
According to above-mentioned fermentation condition and technique, on 10 tons of tanks, carry out 3 batch fermentation tests, fermentation unit is respectively: 3080ug/mL, 3100ug/mL, 3200ug/mL.
Fermented liquid can adopt another invention technology of the applicant, and (application number 201110266790.4, " a kind of knob is Kangding B not for denomination of invention
0extracting and purifying method ") process, obtain macroporous adsorbent resin stripping liquid, carry out chromatography, must purer flow point, collect liquid through concentrating under reduced pressure, resin concentration, flow point is condensed into solid, through pulverizing and being dried to pulverulent solids, is not Kangding B of knob
0.Bacterial strain of the present invention is because fermentation unit is high, and the technique of extraction and purifying is simpler, on large production, is having more advantage.
Embodiment 3: fermentation culture is prepared not Kangding B of knob
0
Adopting deposit number is the bacterial strain of CCTCC NO:M2012475
Shake-flask seed is cultivated: in every 100mL substratum, contain N.F,USP MANNITOL 2g, yeast powder 0.5g, corn steep liquor 0.5g, soybean cake powder 1g, KH
2pO
41g, MgSO
47H
2o 1g, all the other are water, pH nature.Access 5%(V/V) 30% glycerine mycelia freeze pipe, 220rpm, 26 DEG C cultivate 3 days seed liquor.
Seed tank culture: contain N.F,USP MANNITOL 4g in every 100mL substratum, raw bean powder 1.5g, cottonseed meal 0.5g, corn starch 1g, KH
2pO
40.5g, all the other are water, pH nature.Seed inoculum size 0.1%(V/V), 150rpm, cultivates 4 days for 26 DEG C.
Fermentor cultivation: contain N.F,USP MANNITOL 8g, glucose 6g, cottonseed meal 3g, yeast powder 2g, KH in every 100mL substratum
2pO
40.3g, FeSO
47H
2o 0.2g, Serine 0.3g, L-arginine 0.2g, all the other are water, pH7.0.Seed inoculum size 5% (V/V), 180rpm, cultivates 9 days for 26 DEG C.
Putting tank gained fermented liquid tires as 2900ug/mL.
Embodiment 4: fermentation culture is prepared not Kangding B of knob
0
Adopting deposit number is the bacterial strain of CCTCC NO:M2012475
Shake-flask seed is cultivated: in every 100mL substratum, contain maltodextrin 1g, and yeast powder 1g, cottonseed meal 1g, urea 2g, all the other are water, pH7.0.Access 3%(V/V) 30% glycerine mycelia freeze pipe, 250rpm, 24 DEG C cultivate 3 days seed liquor.
Seed tank culture: in every 100mL substratum, contain maltose 1g, potato dextrin 1g, silkworm chrysalis hydrolyzed solution 0.3g, cottonseed meal 0.5g, corn starch 0.2g, all the other are water, pH7.0.Seed inoculum size 0.2%(V/V), 180rpm, cultivates 4 days for 22 DEG C.
Fermentor cultivation: in every 100mL substratum, contain glycerine 4g, glucose 4g, cottonseed meal 0.5g, yeast extract powder 0.3g, corn starch 0.2g, all the other are water, pH7.0.Seed inoculum size 8% (V/V), 150rpm, cultivates 10 days for 22 DEG C.
Putting tank gained fermented liquid tires as 3132ug/mL.
Embodiment 5: fermentation culture is prepared not Kangding B of knob
0
Adopting deposit number is the bacterial strain of CCTCC NO:M2012475
Shake-flask seed is cultivated: in every 100mL substratum, contain glucose 4g, potato starch 4g, dried silkworm chrysalis meal 2g, raw bean powder 2g, corn starch 4g, MnSO
44H
2o 0.5g, NaNO
31g, K
2hPO
41g, all the other are water, pH nature.Access 5%(V/V) 30% glycerine mycelia freeze pipe, 240rpm, 26 DEG C cultivate 2 days seed liquor.
Seed tank culture: in every 100mL substratum,, containing sucrose 4g, potato leaches powder 4g, yeast powder 3g, dregs of beans 3g, corn starch 1g, Fe (NH
4)
2(SO
4)
26H
2o 1.5g, KNO
31g, all the other are water, pH nature.Seed inoculum size 0.1%(V/V), 200rpm, cultivates 3 days for 24 DEG C.
Fermentor cultivation: contain N.F,USP MANNITOL 8g in every 100mL substratum, glucose 8g, raw bean powder 0.5g, yeast powder 1g, corn starch 0.5g, KH
2pO
40.5g, NaNO
30.5g, TYR 0.5g, L-threonine 0.5g, 1B 0.5g, L-Leu 0.5g, all the other are water, pH7.2.Seed inoculum size 15% (V/V), 200rpm, cultivates 9 days for 26 DEG C.
Putting tank gained fermented liquid tires as 2902ug/mL.
Claims (7)
1. fungi (Glarea lozoyensis) FIM2006071, by the center preservation of Chinese Typical Representative culture collection, preserving number is CCTCC NO:M2012475, preservation date is: on November 23rd, 2012.
2. preserving number as claimed in claim 1 is that the bacterial strain of CCTCC NO:M2012475 is prepared not Kangding B of knob in fermentation
0in application.
3. to require the preserving number described in 1 be that the strain fermentation of CCTCC NO:M2012475 is prepared not Kangding B of knob to application rights
0method, it is characterized in that comprising the following steps:
A, it is the bacterial strain of CCTCC NO:M2012475 that fermentation strain adopts deposit number;
B, the inoculum size of 30% glycerine mycelia freeze pipe of preparation according to a conventional method being pressed to the 3-5% of shake-flask seed culture volume accesses shake-flask seed substratum, and 220-260rpm cultivates 2-3 days, obtains shake-flask seed liquid; Shake-flask seed liquid is inoculated in to seeding tank by the inoculum size of the long-pending 0.1-0.2% of seed tank culture matrix, and 120-200 rpm, cultivates 3-4 days, obtains tank seed liquor; Tank seed liquor is inoculated in to fermentation tank culture medium by the inoculum size of the 5-15% of fermentation volume, 150-200rpm, fermentation culture 9-12 days, collects fermented liquid; Wherein culture temperature is 22-26 DEG C.
4. fermentation preparation as claimed in claim 3, is characterized in that:
The ratio of the each component of shake-flask seed substratum in substratum is: in every 100mL substratum, and carbon source 1-8g, nitrogenous source 2-8g, inorganic salt 0-2.5g, all the other are water;
The ratio of the each component of seed tank culture base in substratum is: in every 100mL substratum, and carbon source 2-8g, nitrogenous source 1-7g, inorganic salt 0-2.5g, all the other are water;
The ratio of the each component of fermentation tank culture medium in substratum is: in every 100mL substratum, and carbon source 8-16g, nitrogenous source 1-5g, inorganic salt 0-1g, amino acid 0-2g, all the other are water.
5. fermentation preparation as claimed in claim 4, the preferred proportion of the each component of substratum in substratum is:
The ratio of the each component of shake-flask seed substratum is: in every 100mL substratum, and carbon source 2-4g, nitrogenous source 4-6g, inorganic salt 1-2g, all the other are water;
The ratio of the each component of seed tank culture base is: in every 100mL substratum, and carbon source 4-6g, nitrogenous source 3-5 g, inorganic salt 0.5-1.5g, all the other are water;
The ratio of the each component of fermentation tank culture medium is: in every 100mL substratum, and carbon source 10-14g, nitrogenous source 2-4g, inorganic salt 0.3-0.5g, amino acid 0.5-1.5g, all the other are water.
6. the preparation method as described in claim 4 or 5, the each component of wherein said substratum is: carbon source is selected from potato starch, W-Gum, Zulkovsky starch, maltodextrin, potato dextrin, and glycerine, glucose, maltose, murphy juice, potato leach one or more in powder, N.F,USP MANNITOL; Nitrogenous source is selected from one or more in soybean cake powder, raw bean powder, dregs of beans, corn steep liquor, corn starch, silkworm chrysalis hydrolyzed solution, urea, ammonium sulfate, yeast powder, yeast extract powder, cottonseed meal, dried silkworm chrysalis meal; Inorganic salt are selected from K
2hPO
4, MnSO
44H
2o, NaCl, Fe (NH
4)
2(SO
4)
26H
2o, NaNO
3, KNO
3, MgSO
47H
2o, FeSO
47H
2o, KH
2pO
4in one or more; Amino acid is selected from one or more in 1B, L-Leu, ILE, TYR, L-threonine, Serine, L-PROLINE, L-arginine.
7. preparation method as claimed in claim 6, wherein said medium optimization is: carbon source is one or more in glucose, N.F,USP MANNITOL; Nitrogenous source is one or more in yeast extract powder, corn starch, yeast powder, cottonseed meal, raw bean powder; Inorganic salt are KH
2pO
4, K
2hPO
4, MnSO
44H
2o, FeSO
47H
2one or more in O; Amino acid is one or more in L-PROLINE, L-threonine.
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| CN108265096B (en) * | 2016-12-30 | 2021-11-16 | 江苏恒瑞医药股份有限公司 | Preparation of pneumocandin B by microbial fermentation0Method (2) |
| CN106755223A (en) * | 2017-01-20 | 2017-05-31 | 信泰制药（苏州）有限公司 | A kind of fermentation process of Pneumocandin B0 |
| CN106755225B (en) * | 2017-01-20 | 2020-06-26 | 信泰制药（苏州）有限公司 | Fermentation method of pneumocandin B0 |
| CN107201316B (en) * | 2017-07-14 | 2020-04-07 | 海正药业(杭州)有限公司 | Aspergillus and producing pneumocandin B thereof0Method (2) |
| CN108048512B (en) * | 2018-01-24 | 2022-04-08 | 湖南唯创前沿科技有限公司 | Fermentation method for preparing pneumocandin B0 |
| CN115747283A (en) * | 2021-09-03 | 2023-03-07 | 杭州中美华东制药有限公司 | Method for preparing pneumocandin B0 through fermentation |
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