US3626055A - Method for producing antibiotic t-2636 - Google Patents

Method for producing antibiotic t-2636 Download PDF

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US3626055A
US3626055A US730113A US3626055DA US3626055A US 3626055 A US3626055 A US 3626055A US 730113 A US730113 A US 730113A US 3626055D A US3626055D A US 3626055DA US 3626055 A US3626055 A US 3626055A
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percent
antibiotic
test
soluble
methanol
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Eiji Higashide
Motoo Shibata
Setsuo Harada
Toyokazu Kishi
Komei Mizuno
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TAKIDA CHEMICAL IND Ltd
TAKIDA CHEMICAL INDUSTRIES Ltd
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TAKIDA CHEMICAL IND Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
    • C12P1/04—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes by using bacteria
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07G—COMPOUNDS OF UNKNOWN CONSTITUTION
    • C07G11/00—Antibiotics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/886—Streptomyces

Definitions

  • FIGS PATENTEU 05c 119m 0 O O O 0 w 8 6 4 2 METHOD FOR PRODUCING ANTIBIOTIC T-2636 This invention relates to antibiotically active novel compounds and to the production thereof.
  • this invention relates to a group of antibiotics T-2636-A, T-2636-B, T-2636-C, T-2636-D and mixtures thereof (hereinafter, including also the claims, each of these antibiotics or a mixture of them is collectively referred to as antibiotic T-2636).
  • the invention is based on the following findings:
  • micro-organisms capable of producing the new antibiotics are isolated from soil samples
  • micro-organisms belong to the genus Streptomyces
  • so-accumulated antibiotics can be recovered in a desired purity from the culture broth by taking advantage of the physico-chemical properties of the antibiotics;
  • the antibiotics have a strong antimicrobial activity against Gram positive bacteria.
  • those micro-organisms belonging to the genus Streptomyces and capable of producing the antibiotic T-2636 are employed. These microorganisms include Strain No. T-2636 which has been isolated from a soil sample in Osaka, Japan, and mutants thereof.
  • Sporophores show monopodial branching and pseudoverticillus, and form loops or spirals with spores arranged in chains.
  • Spores are oval or ellipsoidal with a smooth surface, ranging from 0.5 to 1.0 p. by 0.9 to 1.5 p. in size.
  • the substrate mycelia are colorless.
  • the strain forms brown to brownish gray aerial mycelia, produces no soluble pigments on almost all kinds of media or merely produces faint yellowish pigment, and belongs to the nonchromogenic type.
  • the temperature for growth is from about 20 to about 45 C. atapHofS to9.
  • Aerial mycelia poor, powdery, white to Light Drab (Rdg.
  • Soluble pigment none.
  • Aerial mycelia poor, white to Light Drab (Rdg. XLVl,
  • Soluble pigment none.
  • Aerial mycelia poor, powdery, white to Light Cinnamon Drab (Rdg. XLVl, 13""b) to Light Drab (Rdg. XLVl, l7""-b).
  • Soluble pigment none.
  • Aerial mycelia abundant, powdery and Light Drab (Rdg. XLVl, 17""b) to Drab (Rdg. XLVl, 17"") or Drab Gray (Rdg. XLVl, 17""-d) interspersed with white patches.
  • Soluble pigment none.
  • Aerial mycelia poor, white or sometimes Light Drab (Rdg.
  • Glycerin nutrient agar Growth: abundant, folded, colorless to pale yellowish brown.
  • Aerial mycelia fairly good, white.
  • Soluble pigment none or pale yellow pigment produced.
  • Aerial mycelia none or poor, white.
  • Soluble pigment none.
  • Aerial mycelia none or scant, white. Reverse: colorless.
  • Soluble pigment none.
  • Aerial mycelia fairly abundant, white to Drab Gray (Rdg.
  • Soluble pigment none.
  • Aerial mycelia abundant, white to Pale Olive Gray (Rdg. Ll, 23""'-f) or Mouse Gray (Rdg. L], 15"') to Drab Gray (Rdg. XLVl, l7"d).
  • Soluble pigment none.
  • Aerial mycelia abundant, white to Drab Gray (Rdg. XLV],
  • Soluble pigment none.
  • Aerial mycelia abundant, powdery, white to Light Drab (Rdg. XLVl 17""-b) to Drab(Rdg.XLVl,17"").
  • Soluble pigment none.
  • Aerial mycelia poor, white.
  • Soluble pigment none.
  • Aerial mycelia none or scant, Drab Gray (Rdg. XLVl,
  • Soluble pigment none.
  • Aerial mycelia poor, white to gale Drab Gray (Rdg. XLVl,
  • Soluble pigment none.
  • Aerial mycelia none or scant, Drab Gray (Rdg. XLVl,
  • Streptomyces rochei forms straight or spiral sporophores, produces pale yellow soluble pigments with rapid liquefaction on gelatin, reddish brown pigments on potato plug and shows brown growth on starch medium, while Strain No. T-2636 produces loop or spiral sporophores, shows no soluble pigment nor liquefaction on gelatin and is almost colorless on potato plug, colorless on starch medium.
  • Strain No. T-2636 is considered to be a variant of Streptomyces rochei and has been named Srreptomyces rochei var. volubilis, a culture of which has been deposited at American Type Culture Collection, Rockville, Maryland, USA. under the accession number of ATCC-2l250.
  • mutants and variants of T-2636-producing organism There are many mutants and variants of T-2636-producing organism.
  • mutants and variants of T-2636-producing organism regardless of whether the variation is caused naturally or artificially, for example, with X-ray, ultraviolet-ray, or by the action of chemical reagents such as nitrogen mustard, nitrosoguanidine or salts of heavy metal, any one can be employed in the method of the present invention, as long as it produces antibiotic T-2636.
  • the main object of the present invention is to produce a novel antibiotic T-2636.
  • Another object of the present invention is to provide a method for producing the said antibiotic.
  • the objects of this invention are realized by incubating a T-2636-Streptomyces in a medium containing assimilable carbon sources, digestible nitrogen sources and other nutrients, and recovering the accumulated antibiotic T-2636 therefrom.
  • this can be liquid or solid, but submerged culture using aerated agitation method is most advantageous.
  • the culture conditions such as temperature, culture period and pH of the medium are determined so that the strain of micro-organism being used grows luxuriantly and the output of the antibiotic T-2636 is maximum.
  • the medium is preferably maintained at a pH of 6 to 8 and the optimum incubating temperature lies between about 24 and 40 C. and, for better results, between about 28 and about 37 C.
  • the antibiotics T-2636-A, -B, C and D are accumulated in the medium in various proportions.
  • T-2636-A and -C are more preferably produced by incubating the T-2636-producing strain in a medium comprising 2 percent of glucose, 3 percent of soluble starch, 1 percent of corn steep liquor, 1 percent of soy bean flour, 0.5 percent of polypeptone, 0.3 percent of sodium chloride and 0.5 percent of calcium carbonate (pH 7.0) for about 42 hours
  • T-2636-B and -D are luxuriantly obtained when the same strain is incubated in a medium including 5 percent of soluble starch, 2 percent of corn steep liquor, 0.5 percent of polypeptone, 0.2 percent of K,HPO,, 0.5 percent of calcium carbonate (pH 7.0) for about 78 to about hours.
  • Antibiotic T-2636 thus produced is contained mostly in the liquid part of the culture broth, but also in the mycelia.
  • These antibiotics are weakly basic or neutral fat-soluble substances, and therefore can be extracted en bloc from the culture broth or its filtrate or the mycelia by the use of a suitable organic solvent.
  • the respective antibiotics can be divided into the several antibiotic T-2636-A, B, -C or -D, utilizing, for example, different adsorbances between the antibiotics.
  • antibiotic T-2636 exists mostly in the liquid part of the culture broth, it is advantageous to separate at first the liquid part of the culture broth from the culture broth.
  • the culture broth is filtered with or without adding a filter aid at a pH between about 3 and about 8 to obtain culture filtrate.
  • the filtrate contains most of the objective antibiotic T-2636 showing antimicrobial activity.
  • the filtrate is extracted at a pH between about 2 and about 9 with a water-immiscible organic solvent such as lower fatty acid ester (e.g. ethyl acetate, amyl acetate), aromatic hydrocarbon (e.g. benzene), chlorinated hydrocarbon (e.g. methylene chloride, chloroform), ketone (e.g.
  • lower fatty acid ester e.g. ethyl acetate, amyl acetate
  • aromatic hydrocarbon e.g. benzene
  • chlorinated hydrocarbon e.g. methylene chloride, chloroform
  • the crude powder is dissolved in a suitable organic solvent such as ethyl acetate, chloroform or a mixture thereof, and is charged on a column packed with silica gel or alumina, followed by elution with benzene, diethyl ether, ethyl acetate, acetone, chloroform, methanol or a mixture thereof, to obtain eluates containing the active components -A, -B, -C and -D in this order.
  • a suitable organic solvent such as ethyl acetate, chloroform or a mixture thereof
  • an eluate thus obtained contains plural components among the four, such components can be respectively isolated. Namely, the eluate obtained by the above procedure is concentrated, and the concentrate is again treated with chromatography (e.g. thin layer chromatography or, more industrially, column chromatography) on silica gel or alumina. Thus the objective antibiotics are obtained as pure crystals respectively.
  • chromatography e.g. thin layer chromatography or, more industrially, column chromatography
  • the separation of the active ingredients in mycelia is advantageously achieved, for example as follows:
  • the wet mycelia are subjected to extraction with a 70 percent aqueous acetone or a 70 percent aqueous methanol and the extract is concentrated.
  • the concentrate is extracted with such a solvent as benzene, ethyl acetate, methylene chloride and the like.
  • the extract contains antibiotic T-2636 and respective components can be recovered, for example, by means of chromatography as mentioned above.
  • the aqueous residue is extracted with n-butanol, followed by adding ether, whereby there is obtained a powdery substance showing significant maximum ultraviolet absorptions at the wavelengths of 308, 321, 338 and 355 millimicrons when measured in methanol.
  • the substance has antimold activity and is presumed to be a pentaene.
  • T-2636-A forms white plate crystals melting at 200 to 205 C. (recrystallized from diethyl ether), and its elementary analysis is as follows:
  • the molecular weight measured by osmotic pressure in ethyl acetate is about 490, while according to mass spectrometry measurements, its highest mass number is 441. Thus its molecular weight is about 500, and it has one acetyl group.
  • 1 and has the following absorption bands: 3350(M), 3400(M), 2960(W), 2900(W), 2850(W), 1755(8), 1725(sh), 1720(vs), 1700(8), 1690(8), 1650(W), 1500(M), 1450(W), 1440(W), 1360(M), 1320(M), 1260(vs), 1140(M), 1100(W), 1010(M), 960(M), 950(M), 920(W), 860(W), 810(W), 800(W), 740(W), 680(W), 650(W),620(W),580(W)cm.
  • the molecular weight measured by osmotic pressure method in ethyl acetate is about 851, while according to mass spectrometry measurements, the highest mass number is 850. Thus its molecular weight is about 850.
  • FIG. 2 Infrared absorption spectrum by KBr disc method is shown in FIG. 2, and has the following absorption bands: 3500(8), 2960(8), 2930(M), 1750(vs), 1730(vs), 1710(5), 1630(W), 1460(M), 1380(5), 1340(M), 1250(5), 1220(vs), 1100(5), 1150(8), 1110(8), 1090(5), 1050(8), 1030(5), 1000(vs), 060(M), 940(W), 910(W), 900(W), 000(W), 520(W) cm.”-
  • T-2636-B is positive to Molischs reaction and to the Erythromycin Test, but is negative to the Carbomycin Test.
  • T-2636-solvents as those of T-2636-A.
  • T-2636C is soluble in ethylacetate, acetone, ethanol, methanol, hardly soluble in diethylether, insoluble in n-hexane.
  • T-2636-C is positive to Molischs reaction, but is negative to the ferric chloride reaction, and to the Erythromycin and Carbomycin Tests. Infrared absorption spectrum by RB! disc method is shown in FIG.
  • T-2636-D I T-2636-D forms colorless needles melting at to l9 1 C.
  • the molecular weight measured by osmotic pressure in ethyl acetate is about 509, while by mass spectrometry measurements, its mass number is 459. Thus its molecular weight is about 500.
  • T-2636-D Infrared absorption spectrum of T-2636-D by KBr disc method is shown in FIG. 4 and has the following absorption bands: 3350(s), 3320(vs), 2960(M), 2930(W), 1740(8), 1725(vs), 1705(vs), 1650(vs), 1560(5), 1450(W), 1370(M), 1320(M), 1240(vs), 1200(M), 1170(W), 1130(s), 1080(M), 1040(M), 1020(s), 1010(M), 960(8), 920(W), 880(W), 710(W) cm.
  • T-2636-D is positive to the Carbomycin Test, Molishs reaction, but is negative to the Erythromycin Test, ninhydrin reagent and benzidine reagent.
  • T-2636-D is hardly soluble in diethyl ether, chloroform, ethylacetate, slightly soluble in acetone, easily soluble in methanol or ethanol.
  • BIOLOGICAL ACTIVITIES Antibiotics T-2636 show a fairly strong antimicrobial activity even in a crude state, especially against Gram-positive bacteria. The antimicrobial activities are observed not only in vitro but also in vivo when the test animals are administered the antibiotic T-2636 per 05 or parenterally.
  • T-2636-A, -B, -C and -D are observed on 4-weeks old mice by intraperitoneal injection.
  • T-Z636-A 400 (i.p.) T-2636-B about 400 (i.p.) T-2636-C 400 (i.p.) T-Z636-D 400 (i.p.)
  • T-2636-A 5.04 T-2636-C L56 Triacetyloleundomycin (control) 30 Antimicrobial spectra:
  • test organisms were cultured on bouillon agar at 37 C. for 18 hours. Acid fast bacteria were cultivated on glycerin bouillon agar at 37C. for 40 hours. In case of fungi or yeast, glucose bouillon agar was used as assay medium and the incubation was carried out 40 hours at 28 C.
  • Test organisms A B C D M Bacillus ccreus 50 2O 100 100 Bacillus brevia > 100 20 5 100 100 Mycobacterium aviumc 100 50 100 100 20 M ycabacteriu'm phlei. 100 20 50 100 20 M ycobacterz'um sp. ATCC-607. 100 100 100 100 100 20 Piricularia ory/zae 100 100 100 1-2. 0 Penicillium chrysogenum. 100 100 100 100 100 100 2.0 Aspergillas niger 100 100 100 100 100 2.0 Saccharomyces ccrcvisiae. 100 100 100 100 2. 0 Candida albicans 1 100 100 100 100 100 2.0
  • M Mycelia extract.
  • T-2636-B can be regarded as an antibiotic bearing resemblance to Lankamycin (E. G'a'umann et al., Japanese Patent Publication No. l6700/l962, Helvetica Chimica Acta 43 60l (1960)), but has a melting point, molecular weight, ultraviolet spectrum, infrared spectrum, especially 600-800 cm. value, different from those of the known Lankamycin.
  • T-2636-C can be regarded as an antibiotic bearing resemblance to Lankacidin (E. Gat'imann et al., Japanese Patent Publication Number 16700/1962, Helvetica Chimica Acta 43 601 (1960)).
  • T-2636D bears some resemblance to Bundlin B (Sinichi Kondo et al., supra and Sakamoto et al., supra), but has an elementary analysis and infrared spectrum different from those of Bundlin B.
  • Staphylococci are pyogenic or pus-forming bacteria. They tend to produce circumscribed lesions, e.g. in the form of abscesses and the like, which often occur in the skin. Staphylococci are the cause of furuncles and of carbuncles and other common wound infections.
  • the new products of the present invention are useful in topical preparations for the treatment of this type ofinfection in mammals (dogs, cats, humans, etc.).
  • a useful preparation for topical application to an infection due to Staphylococcus aureaus is as follows:
  • This is topically applied in amount sufficient to cover the wound being treated, with gentle rubbing in, the application being made at least once daily and being repeated several times daily, if necessary or desired.
  • Disinfection is effected by application or spraying of a solution (e.g. methanolic or ethanolic, etc.) containing one of the following itemized components: (1) 200 pg/ml. of T-2636A; (2) 20 ig/ml. of T-2636-C; (3) 50 ugJml. of T-2636-A and 50 g/ml. or (4) 200 pig/ml. of T2636-B and 200 pg/ml. of T-2636-D.
  • a solution e.g. methanolic or ethanolic, etc.
  • EXAMPLE 1 A 2-liter Erlenmyer flask containing 0.5 liter of an aqueous culture medium (pH 7.0) containing 2 percent of glucose, 3 percent of soluble starch, 1 percent of corn steep liquor, l percent of soy bean meal, 0.5 percent of polypeptone, 0.3 percent of sodium chloride, 0.5 percent of calcium carbonate is inoculated with 1 loop of a slant culture of Slreptomyces rochei var. volubilis l.F.O. 12507 ATCC-21250 and incubated at 37 C. on a rotary shaker for about 40 hours. (Note-Percentages in the examples are by weight).
  • 1.5 liters of the culture broth is transferred to a SO-liters tank which contains 30 liters ofa culture medium of the same composition as mentioned above plus 30 grams of soy bean oil as an antifoaming agent, and incubation is carried out at 37 C. under an aeration of an equal volume per minute to the culture medium and an agitation of 180 rotations per minute for 20 hours. l liters of thus-obtained culture broth is used as a seed for the following fermentation.
  • a 200-liters tank containing 100 liters of a culture medium of the same composition and soy bean oil as an antifoaming agent is inoculated under submerged aerobic condition (aeration: 100 liters/minute, and agitation: 200 r.p.m.
  • 100 liters of thus-obtained culture broth is adjusted at pH 5 to 6 and filtered in the presence of a filter aid (e.g. 5 to 10 percent of Hyplo Supercel).
  • 72 liters of the filtrate is adjusted to pH 7, and extracted three times with 24 liters each time of ethyl acetate.
  • 57 liters of the combined extract is washed with water, dried and concentrated below 40 C. in vacuo to obtain 2.25 liters ofa concentrate.
  • the concentrate is successively washed twice with one sixth the volume each time of hydrochloric acid (pH 3), twice with one-sixth the volume each time of water, twice with one sixth the volume each time ofsodium hydroxide (pH 8.5) and twice with one sixth the volume each time of water, and then dried with sodium sulfate overnight.
  • the concentrate thus treated is further concentrated, and thereto is added 1 liter of a mixture of diethyl ether and petroleum ether (1:20) or 1 liter of n-hexane to give 12 grams ofcrude substance.
  • EXAMPLE 2 10 grams of the crude substance is dissolved in 100 ml. of a mixture of chloroform and ethyl acetate (1:1), and is chromatographed on 300 grams of silica gel (0.05 to 0.2 mm.). Elution with 1 liter of diethyl ether or benzene affords antimicrobially inactive yellow substance.
  • EXAMPLE 3 10 grams of the crude yellow powder obtained in the manner as in example 1 is subjected to chromatography utilizing 500 grams of silica gel (0.05 to 0.20 mm.), and washed with 1 liter of benzene to remove impurities, then successively eluted with 1 liter of a series of solvents of benzene and ethyl acetate (8:2),(7:3), (6:4), (5:5), (4:6),(3z7), (2:8) and 1 liter of ethyl acetate, in that order whereupon T-2636A, B, C and -D are obtained in the fractions eluted by the above-mentioned solvent (8:2) and (7:3), (5:5), (4:6) and (3:7), (2:8) and ethyl acetate, respectively.
  • EXAMPLE 4 2 liters ofa seed culture broth obtained in the same manner as in example 1 is transferred to a 200-liter tank which con tains 100 liters of an aqueous medium containing 5 percent of soluble starch, 2 percent of corn steep liquor, 0.5 percent of polypeptone, 0.2 percent of potassium monohydrogenphosphate, 0.5 percent of calcium carbonate (pH 7.0) and 100 grams of silicone as an antifoaming agent. Incubation is conducted at 37 C. under an aeration of an equal volume per minute to the culture medium and an agitation of 200 rotation per minute for 90 hours, while supplying additional 300 grams ofsilicone.
  • a method according to claim 1, wherein the antibiotic is substantially a mixture of at least two members selected from the group consisting of T-2636-A, T-2636-B, T-2636-C and T-2636-D.
  • T-2636-B characterized by the following properties: it forms colorless plate crystals melting at 205 to 207 C.
  • T-2636-D characterized by the following properties:

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US730113A 1967-05-18 1968-05-17 Method for producing antibiotic t-2636 Expired - Lifetime US3626055A (en)

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BE (1) BE715356A (xx)
CH (1) CH513238A (xx)
DE (1) DE1770441C2 (xx)
DK (1) DK117626C (xx)
FR (2) FR1590599A (xx)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2494964A1 (fr) * 1980-11-29 1982-06-04 Takeda Chemical Industries Ltd Traitement perfectionne dans l'elevage des porcs et composition utilisee pour ce traitement
US4480033A (en) * 1982-04-12 1984-10-30 Takeda Chemical Industries, Ltd. Lankacidins production

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4810442B1 (xx) * 1968-10-26 1973-04-03

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2805185A (en) * 1955-05-04 1957-09-03 Du Pont Antibiotic and production thereof
US3344024A (en) * 1963-04-17 1967-09-26 American Cyanamid Co Antibiotic am-684 and method of production

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2805185A (en) * 1955-05-04 1957-09-03 Du Pont Antibiotic and production thereof
US3344024A (en) * 1963-04-17 1967-09-26 American Cyanamid Co Antibiotic am-684 and method of production

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2494964A1 (fr) * 1980-11-29 1982-06-04 Takeda Chemical Industries Ltd Traitement perfectionne dans l'elevage des porcs et composition utilisee pour ce traitement
US4425356A (en) 1980-11-29 1984-01-10 Takeda Chemical Industries, Ltd. Lankacidin derivatives used in swine husbandry
US4480033A (en) * 1982-04-12 1984-10-30 Takeda Chemical Industries, Ltd. Lankacidins production

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DE1770441C2 (de) 1984-12-13
FR1590599A (xx) 1970-04-20
BE715356A (xx) 1968-10-16
DE1770441A1 (de) 1971-10-21
GB1226665A (xx) 1971-03-31
DK117626C (da) 1970-10-19
CH513238A (de) 1971-09-30
DK117626B (xx) 1970-05-19
NL6807119A (xx) 1968-11-19
NL142723B (nl) 1974-07-15

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