Method of producing derivatives of antibiotics a-21978c, strain of streptomyces roseosporus used for

专利摘要:
An improved process is provided for producing A-21978C cyclic peptide derivatives having a C2-C14 alkonoyl side chain which comprises feeding a C2-C14 alkanoic acid, or an ester or salt thereof, to the A-21978C-producing culture during the production stages of the fermentation. In addition, a new process is provided for producing the A-21978C antibiotics which comprises cultivating under aerobic conditions a new strain of microorganism.
公开号:SU1452484A3
申请号:SU853964395
申请日:1985-10-08
公开日:1989-01-15
发明作者:Милтон Хабер Флойд；Льюис Пипер Ричард；Джозеф Титц Энтони；Эдвард Итон Том；Максин Форд Линда；Вебстер Годфри Отис (младший)；Льюис Браун Хабер Мери；Джозеф Цмиевски Милтон (Младший)
申请人:Эли Лилли Энд Компани (Фирма)；
IPC主号:

专利说明:

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This invention relates to microbiology, in particular to the production of antibiotics.
The purpose of the invention is to simplify the method, as well as to create a new strain suitable for the production of antibiotic substances A-21978C.
The Streptomyces roseosporus A-21978.65 strain is a mutant of the Str.roseosporus strain NRRL 11379, deposited under the number NRRL 15998 and is characterized by the following features.
Cultural and morphological features.
Spore chains contain more than 10 spores per chain. The spore surface is smooth from oblong to oval. Sporophores are straight to winding. The size of the dispute 0.85x1.78 microns (medium).
Carrot plugs: aerial mycelium - good growth, color gray with scarlet, substrate - stable growth, color brown. Soluble pigments are absent.
Potato plugs: aerial mycelium - good growth, gray with scarlet color, substrate mycelium - abundant growth, brown color. Dark brown soluble pigment.
YSP No. 1: aerial mycelium - mediocre growth, color (W) a white (color by Maeg and Paul), substrate mycelium - good growth, color (10A1) is pale yellow-green. Soluble pigment is missing.
YSP No. 2: aerial mycelium plentiful, (R) 5 with a gray-yellow-pink, substrate mycelium - abundant. (5D10 light red-brown. Soluble pigment of light brown color
U5R No. 3: AIR mycelium mediocre, (W) a white, substrate mycelium mediocre, (10A2) pale yellow-pink. Light brown soluble pigment.
Y8R No. 4: aerial mycelium is good, (W) b is white, substrate mycelium is good, (10B1) is pale yellow-green. Light brown soluble pigment
ySP No. 5: aerial mycelium mediocre, (W) 13Ba purple-white, substrate mycelium good, (377) gray yellow-pink. Soluble pigment grayish-pink color.
ySP No. 7: copious air mycelium, (R) 5cb gray yellow-pink. Ra
about
five
0
five
P
.
five
0
0
five
dark brown pigment.
. Modified Bennett agar: substrate mycelium poorly developed, pale yellow-brown. Soluble pigment and aerial mycelium are dried.
Malate-calcium agar: aerial mycelium is not developed, substrate mycelium is mediocre, (7L12) red-brown. Light brown soluble pigment.
Agar Čapek: aerial mycelium poorly developed, (W) a white, substrate mycelium poorly developed, whitish. Soluble mycelium is absent.
Emerson agar: aerial mycelium poorly developed, abundant substrate mycelium, (). Soluble pigment is missing.
Glucose-aspartic agar: aerial mycelium good (W) white, substrate mycelium good, (12В2) gray-yellow. Soluble pigment is missing.
Glycerin-glycine agar: aerial mycelium is poorly developed, substrate mycelium is abundant, (8L12) dark gray brown Soluble pigment of brown color
Nutrient agar: aerial mycelium is absent, substrate mycelium is poorly developed, pale yellow-gray Soluble pigment is absent.
Agar on tomato paste and oat flour: copious air mycelium, (R) 5cb gray-yellow-pink, substrate mycelium Copious, (8L12) dark gray-brown. Soluble pigment brown.
Physiological and biochemical properties.
Among carbohydrates, it uses L-arabinose, D-fructose, D-galactose, D-glucose, D-mannitol, L-rhamnose, salicin, D-xylose, does not absorb i-inositol, D-raffinose, sucrose.
Melanoid pigments do not form. Gelatin thins. Tyrosine test is negative. Grows in the presence of 10% NaCl.
Unloaded milk produces weak hydrolysis. Starch hydrolyzes nitrates to nitrites does not restore.
The pH range of growth is 5-11.
Growth temperature range 25 -.
Sensitive to antibiotics: erythromycin (15 μg / disk), cephalothin (30 μg / disk), polymyxin B (300 units / disk), streptomycin (10 μg / disk), tetracycline (30 μg / disk), vancomycin (30 µg / disk).
The strain produces antibiotic substances A-21978S.
The use of Str.roseosp rus NRRL 15998 and NRRL 11379 strains is illustrated by the following examples.
Example. Preparation of complex A-21978C.
A pure culture is obtained and maintained in the first phase of liquid nitrogen. StToToseosporus NRRL 15998, previously stored in the vapor phase of liquid nitrogen, is used to inoculate 50 ml of vegetative medium of the following composition,%:
Soy broth
Trypticase. 3.0
Dextrin 2.5 Deionized water 94.5
The inoculated medium is incubated in a 250 ml Erlenmeyer flask at 30 ° C for 48 hours on a shaking apparatus, rotating through an arc of 2 inches in diameter (51.4 mm) at a speed of 250 rpm. Mature vegetative culture is distributed into multiple containers (0.5 MP / container) and stored in liquid nitrogen vapors.
1 ml of the culture stored in liquid nitrogen was used to inoculate 80 ml of the above vegetative medium. The inoculated vegetative medium is incubated in a 250 ml Erlenmeyer flask at 30 ° C for 48 hours on a shaking apparatus, rotating at 250 rpm
10 ml of this culture is used to inoculate 450 ml of medium for the second stage of vegetative growth, having the same composition as the above-described primary vegetative medium. The medium for the second stage is incubated in a two-liter Erlenmeyer flask for 24 hours at 30 ° C on a shaking apparatus, rotating with speed of 250 rpm
1 liter of second stage vegetative culture is used to inoculate 39 l of sterile medium following composition,%:
0
o
0
Soybean flour O, 5 Yeast extract0, 5 Calcium gluconate 1, 0 Potassium chloride 0.02 MgS04-7H20 0.02 FeS04 7H20 0,0004 Sag 471 (anti-foaming agent) 0.03 Water. 97.9296 Trace minerals (potassium chloride, MgS04-7H20, FeSO 7H20) were prepared as follows: FeSO. 7NO (7.6 g) was dissolved in concentrated hydrochloric acid (76 ml). MgSO 7H.jO (380 g), KCl (380 g) and deionized water were added to obtain a total volume of 3800 ml. Specific minerals use 80 ml of solution per 39 liters of inoculum and tertiary stage of development.
The inoculated medium is incubated for 24 hours in a stainless steel vessel at. The vessel is aerated with sterile air at an air flow rate of 0.85 v / v / min and stirred with a conventional stirrer at a speed of 350-450 rpm.
1 liter of the incubated inoculum of the third stage of development is used to inoculate 1I9 l of sterile g-producing medium of the following composition,%:
Soya flour 2,2 Fe (NH4) iS04 6H20 0.066 Dextrose, 0.825
Sag 4710,022
Potato
dextrin3,3
Molasses (dark wine) 0,275
5 Plumbing
water93,312
five
The pH is adjusted to 7.0 after the first two ingredients are added and 50 again after all the ingredients have been added, just before sterilization.
The gg-producing inoculated medium is incubated for 6 days in a stainless steel vessel at 20 ° C and aerated with sterile air with an air flow rate of 0.5 v / v min. The medium is stirred with an ordinary stirrer.
at a speed of 250 rpm during the first 15 hours and at a speed of 350 rpm after 15 hours. pH is maintained at or above 6.5 by adding G
The increased receptacle medium is added sterile. A solution consisting of 25% (v / v) nonanoic acid and 75% measurement. A-21978Cj.
The primary, secondary, and tertiary stages of cultivation are carried out as the AO of the tiloleate, with a flow rate of 0.13 ml per liter described in Example 1, the fermentation broth at 1 hour and the step of initiating production, keep this flow until the end as described in the example 1, during fermentation after 144 h. The yield, except that, starting from 28 h, lex A-21978C is 0.821 g per 1 liter of broth is added to the fermentation medium — an increase of 293% of 50% compared with the yield obtained in - (volume-volume) caprylic (octane)
Example 1. Factor A-21978Cd (formula (1: K nonanoyl)) is 10% of the total amount of complex A-21978C obtained by this method in complex A-21978C obtained by the method described in Example 1, factor A- 21978С9 not found
acid and methyl oleate, with a flow rate of 0.13 ml per 1 liter of fermentation broth per hour, and this flow rate is maintained until after fermentation after 144 hours. The yield of complex A-21978C is 1.255 g per 1 liter of broth, i.e. 455% more than the yield in Example 1. Factor A-21978Cj (compound of formula I., in which R is octanoyl) represents 9% of the total amount of complex A-21978C obtained by this method, in complex obtained by the method described in the example. re 1, A-21978C is not detected.
PRI me R 3 Increased receipt of A-21978S9.
The primary, secondary, and tertiary stages of development of the inoculite are performed as described in Example 1. The production step was initiated as described in Example 1, except that, starting at 28 hours, in the fer
no ammonium hydroxide solution. The yield of complex A-21978C of formula I is 0.282 g per liter of broth at the end of fermentation.
/
 I H /
N 1 N
/ H,
sterilization medium is added sterile-. 25% (v / v) of nonanoic acid and 75% methyl oleate at a flow rate of 0.13 ml per liter of fermentation broth per hour and maintain this flow until 144 hours after the fermentation is completed. L-A-21978C is 0.821 g per liter of broth — an increase of 293% compared to the yield obtained in -
40 d
Example 1. Factor A-21978Cd (formula (1: K nonanoyl)) is 10% of the total amount of complex A-21978C obtained by this method in complex A-21978C, obtained by the method described in Example 1, factor A-21978C9 Not found
PRI me R 4o Increased production of factor A-21978C (formula I R - n-decanoyl) ..

The primary and secondary stages of vegetative growing are performed as described in Example 1. At the tertiary stage, 800 ml of secondary culture of the inoculum is used to inoculate 950 liters of sterile medium for the tertiary growth of the inoculum of the following composition,%:
Dextrose2.0
Calcium carbonate 0, 2 Soem flour 2.0
Yeast
extract, 1
KC10.02
MgSO7H20 0.02 FeS04 lHjO 0.0004 Sag 471 (anti-foaming agent) 0.02 Water 95.6396
A solution of trace minerals (KC1, MgS04-7HiO, FeS04 7H, jO) was prepared in the same way as described in Example 1. The inoculated medium was incubated for 24 hours in a stainless steel vessel. The vessel is aerated with sterile air with an air flow rate of 0.8 v / v / min and stirred with a conventional stirrer. 1 l of this inoculum of the tertiary stage is used to inoculate 119l of the medium at the production stage, having the composition given in Example 1. The production stage is also initiated as described in Example 1, except that, starting from 28 hours, the fermentation - the medium is supplied with a sterile solution consisting of 50% (v / v) caproic (decanoic) acid and 50% of methyl oleate at a flow rate of 0.26 ml / l of fermentation broth per hour, and this flow rate is maintained until the end of the fermentation process 283 h. The yield of complex A-21978C is 1.94 g per liter of broth. and is 687% more yield achieved in Example 1. The concentration of factor A-21978Cfo (formula I: R - n-decanoyl) is 1.63 g per 1 liter or 84% of the total amount of complex A-21978S. This is 13583% more than the amount of A-219780, obtained by the method described in example 1.
EXAMPLE 5: Variant of the method for increasing production A-21978C, j.
The primary, secondary and tertiary stages of development of the inoculum are performed in the same manner as described in Example 1. The production step was initiated in the same manner as described in Example 1, except that, starting from 28 hours, a sterile solution is added to the fermentation medium. consisting of 25% (v / v) ethyl (complex) ester of caproic acid (ethyl caprat) and 75% methyl oleate, at a flow rate of 0.13 ml / l of fermentation broth per hour, and maintain this flow rate until the end of the fermentation process after 144 h. The output of complex A-21978C is 1.022 g / l increase in n and 362% compared with the yield achieved in Example 1. The concentration of factor A-21978 ° C is 0.202 g / l, or 20% of the total amount of complex, A-21978 ° C.
EXAMPLE 6 Ba: A variant of the method of increased production of A-21978C,.
The primary and secondary stages of vegetative growth are carried out as described in Example 1. The tertiary stage of inoculation is carried out as described in Example 4,
with the exception that the volume of the medium is 1900 liters and the duration of the stage is increased to 48 hours. The aeration rate is 0.3 ° & / vol. in 1 min during the first 24 h, 0.45 v / v. in 1 min in
24-40 hours and 0.90 v / v. 1 minute for 40-48 hours. The stage of production was initiated as described in example 1. After 23 hours, 0.004% of the yeast extract was introduced into the fermentation medium, and starting from 36 hours - a solution of glycerol and ammonium decanoate at a flow rate of 0.84 ml / l of fermentation broth per 1 hour. The nutrient solution contains glycerin (3600 g), deionized water (9000 ml), caproic acid (-1 l) and concentrated ammonium hydroxide solution (630 ml). Consumption is maintained at this level until fermentation is complete (143 hours). The yield of complex A-21978C is 1.722 g / l. The concentration of factor A-21978C, d is 0.739 g / l, or 42% of the total amount of complex A-21978C.
Example7. Increased receipt of A-21078S, 1.
The primary, secondary and tertiary stages of the preparation of the inoculum are carried out as described in Example 1. Step
production was initiated as described in Example 1, except that, starting at 28 hours, a sterile solution of 25% (v / v) was introduced into the fermentation medium.
undecanoic acid and 75% methyl oleate, at a flow rate of 0.13 ml per 1 liter of fermentation broth at 1 hour before the end of the fermentation process after 144 hours. The yield of complex A-21978 ° C is 1.62 g / l. The concentration of factor A-21978C ,, (formula I: R - undecanoyl) is 0.70 g / l or 43% of the total amount of complex A-2I978C. In the complex A-21978S, obtained by
the method described in example 1, factor A-2I978C ,, not detected.
Example Increased receipt of A-21978S.
The primary, secondary and tertiary cultivation stages of the inoculum are performed in the same manner as described in Example 1. The production step was initiated in the same manner as described in Example 1, except that, starting from 28 hours, a sterile solution was introduced into the fermentation medium. consisting of 25% (volume-volume) lauric acid and 75% methyl oleate, with a flow rate of 0.13 ml / l of fermentation broth at 1 hour before the end of fermentation after 144 hours. The yield of complex A-21978 ° C is 1, 12 g / l The concentration of factor A-21978 Su (formula I: R - dodecodoyl) is 0.372 g / l, or 33% of the total amount of complex A-21978 ° C.

Example 9: Preparation of the complex A-21978C. Complex A-21978C was obtained according to the method described in Example 1, but with the use of a Streptomyces culture: roseosporusNRRL 11379.
U52484
ten
ten
PRI me R 10. A variant of the method of increased production of A-21978C, o
. Get antibiotics A-2I978C,
then according to the method described in example 6,
but using cul-ura Streptomy-ces roseosporus NRRL H379.
Example II Preparation of complex A-21978C in a shake flask.
The procedure described in Example 1 is used, but under the conditions of a boiling flask - my flask using the following fermentation medium, g / l:
Glucose7.5
15 Dextrin30
Casein hydrolyzed with enzyme5
Peptone5
20 Molasses2.5
Deionized water up to 1 l
The yield of complex A-2J978C on this fermentation medium is 25 to 1800 µg / ml of broth.
Table 1 presents the infrared absorption spectra of complex A-21978c and factors (in the form of sodium salts, tablets of 30 potassium bromide).
Table 1
Continued tabl, 1
13
Continuation of taOl.
UV (HjO), 220 (46,250) U25 em characteristics similar to 249 (8550); 255 (10,500); 261 A-21978Сс. (E 10,250); 264 (f 4950); 288
(4,000); 264 (4000). The use of the invention allows the Amino-acid analysis to be given in the preparation of both the antibiotic complex 4. Table 4 is a leuke and derivatives of antibiotic factors in a simpler way.

权利要求:
Claims (1)
[1]
Invention Formula
,, .. -СНт НООС Х-
NO
he,
II I
./.N
1 II ./
0- /, / ./0
. about
  NZS-Ch-n
H
0

sh
// I NT (
Oh H - N (I N.
 . N
about
 X
about
H
14
Continuation of table 4
35
1 "Method for producing A-21978C antibiotic derivatives of the formula
he,
II I
./.N
1 II ./
about
H II
H CONHi
N II NH-R
- / xh x
I and NJI 5;
fill 1. ..
 ABOUT
SOGN
H
J
H
.X
.n.
15 52484,
where R is a Cg-C, 2 alkanoyl group, and caprylic acid, followed by
characterized in that by isolating the desired product,
in order to simplify the method, strain2. Pop-up method 1, which is different from Streptomyces roseosporus NRRL 15998. Also, with the fact that the Cg or NRRL 11379 used is cultivated in pit-C ,, the alkane acid is a caprotal medium containing a source of new acid, nonanoic acid,
carbon, nitrogen and mineral salts with undecanoic acid, lauric acid under aeration and stirring conditions with vlota or their ether or salt,
the presence of methyl oleate and the corresponding 3-Strain of Streptomycete Streptomy with the present Cg-C, j-alkanoic acid or es roseosporus NRRL 15998, using ethyl caproic ester, which can be used to obtain antibiotic
or ammonium salts of caproic acid A-21978C.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US65897984A| true| 1984-10-09|1984-10-09|

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