WO2008020474A1 - Procédé de production de poudre de colistine en vrac - Google Patents

Procédé de production de poudre de colistine en vrac Download PDF

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Publication number
WO2008020474A1
WO2008020474A1 PCT/JP2006/316057 JP2006316057W WO2008020474A1 WO 2008020474 A1 WO2008020474 A1 WO 2008020474A1 JP 2006316057 W JP2006316057 W JP 2006316057W WO 2008020474 A1 WO2008020474 A1 WO 2008020474A1
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WO
WIPO (PCT)
Prior art keywords
colistin
producing
powder
strain
bulk powder
Prior art date
Application number
PCT/JP2006/316057
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English (en)
Japanese (ja)
Inventor
Kazuyuki Sakamoto
Takashi Miyashita
Toshiaki Nagasato
Masataka Kawahigashi
Original Assignee
Meiji Seika Kaisha Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Meiji Seika Kaisha Ltd. filed Critical Meiji Seika Kaisha Ltd.
Priority to CN200680028123XA priority Critical patent/CN101296938B/zh
Priority to PCT/JP2006/316057 priority patent/WO2008020474A1/fr
Publication of WO2008020474A1 publication Critical patent/WO2008020474A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/07—Bacillus
    • C12R2001/12—Bacillus polymyxa ; Paenibacillus polymyxa

Definitions

  • the present invention provides a novel strain in which coloring of a culture solution is greatly reduced as compared with a production strain used for conventional colistin fermentation production, and uses this as a colistin-producing strain.
  • the present invention relates to a production method for obtaining colistin powder having a high whiteness without performing a decolorization step.
  • Colistin is a peptide antibiotic that acts widely on bactericidal bacteria against Gram-negative bacteria.
  • Bacillus genus Bacillus genus (Bacillus polvmvxa), which is mainly a natural raw material containing a large amount of starch that can be obtained at low cost, is used.
  • the method of fermentative production is known! / Speak (see Patent Documents 1 and 2).
  • the color standard for colistin powder is It is defined as “white or almost white”.
  • a decolorization step such as using carbon for the purification step was necessary.
  • the time required for the production increases, and the recovery rate of the colistin powder, which is the target substance, is reduced.
  • Patent Document 1 JP-A-58-47493
  • Patent Document 2 JP-A-58-129993
  • An object of the present invention is to provide a method for producing a colistin bulk powder having a high whiteness level that is capable of performing a decoloring step that is necessary in a conventional method for producing a colistin bulk powder.
  • the present invention is as follows.
  • Bacillus polymixer bar 'Collisteus which can produce bulk bulk powder with an absorbance of 0.15 or less of 5% concentration (WZV) aqueous solution at 400 nm.
  • a novel production strain useful in a method for producing colistin bulk powder can be provided. Furthermore, by using the strain of the present invention as a production strain, it is possible to provide a method for producing colistin powder having a high degree of whiteness without performing a decolorization step that is essential in the conventional method for producing colistin powder.
  • FIG. 1 shows the absorbance at 300 to 600 nm of the culture filtrate derived from 202-71 strain and the culture filtrate derived from M50 strain obtained in Example 1.
  • FIG. 2 shows a chart obtained by analyzing a solution of colistin bulk powder derived from M50 strain obtained in Example 3 in deionized water by liquid chromatography (HPLC).
  • Bacillus polymixer 'Bar Collistinius (Bacillus polvmvxa var. Colistinus) M50 is an independent administrative agency, National Institute of Advanced Industrial Science and Technology. , Receipt number: FERM ⁇ -10656 (deposited on 11 August 2006: original deposit: FERM ⁇ -20553, original deposit date: internationally based on the Budapest Treaty from 31 May 2005) Transfer to deposit).
  • the production strain used in conventional colistin fermentation production was subjected to artificial mutation treatment to obtain the desired production strain.
  • the artificial mutation treatment method is not particularly limited as long as it is an artificial mutation treatment.
  • ⁇ -methinole ⁇ one-trow ⁇ --trosoguanidine (NTG), ethyl methanesulfonate, etc.
  • Mutation treatment methods such as chemical methods using mutagens; physical methods such as ultraviolet irradiation and X-ray irradiation; biological methods such as genetic recombination and transposon can be used.
  • the bacterial group obtained by the mutation treatment was subjected to liquid culture using a flask and screened using the coloration degree of the culture and the ability to produce colistin as indicators.
  • the degree of coloring is based on the value obtained by measuring the absorbance at 400 nm of the filter paper filtrate of the culture solution.
  • the colistin production ability is based on the value obtained by analyzing the filter paper filtrate of the culture with HPLC. In this way, the degree of coloration was significantly reduced compared to the conventional production strain, and the production strain Bacillus polymixer bar 'Colistinus having the same or higher colistin production ability was obtained. .
  • a strain having a clearly high whiteness of the colistin bulk obtained by producing colistin from Bacillus' polymixer 'Baichi' colistus can be used.
  • a colistin powder having an absorbance of a 5% concentration (WZV) aqueous solution at 400 nm of 0.15 or less, preferably 0.087 or less, more preferably 0.070 or more and 0.087 or less is obtained.
  • Any polymixer 'bar' colistius can be used in the present invention.
  • production strains that can be used in the present invention include subcultured strains, mutant strains, and genetically modified strains of these strains.
  • the color tone of colistin powder produced without performing a decolorization step using carbon or the like from a culture solution produced by fermentation using the M50 strain which is an example of the production strain of the present invention, is a culture derived from a conventional production strain. Compared with the color tone of colistin powder produced by the hydraulic decolorization process, the whiteness is clearly higher. In other words, by using the M50 strain obtained in the present invention as a production strain, it is possible to obtain a colistin powder having a high degree of whiteness without performing a decolorization step that was essential in the conventional method for producing a colistin powder. It becomes.
  • a decolorization step is performed by culturing Bacillus polymixer 'Bar' colisius, adsorbing the culture to ion exchange resin, elution, concentrating and drying. It is possible to produce a colistin bulk powder in which the absorbance of a 5% concentration (WZV) aqueous solution at 400 nm is 0.15 or less. This makes it possible to produce a colistin powder that passes the color standard “generally white” of the European Pharmacopoeia, which is the quality standard for colistin powder used in pharmaceuticals in Europe (including veterinary drugs). In addition, the power that usually required a decoloring step such as adding carbon such as activated carbon, stirring and filtering, and the like.
  • the bulk colistin in the present invention is generally used as a polymyxin peptide antibiotic. Contains known colistin. As for colistin, colistin A having the following structure and colistin B having a similar amino acid structure are known.
  • the colistin bulk powder of the present invention is a crude extract containing colistin to the extent that it can be used as a pharmaceutical product, and is obtained without going through a decolorization step as described above.
  • the method for using the colistin powder is not particularly limited, and can be used as it is, or further processed and used as a colistin preparation.
  • the M50 strain was selected as a strain that is equivalent to or better than the colistin producing ability of 202-71 strain and the color of the filtrate is clearly lighter than that of 202-71 strain.
  • Absorbance at 300-600 nm was measured for the culture filtrates of 202-71 and M50 strains using a spectrophotometer, and the results are shown in FIG.
  • the absorbance at 400 nm was 3.61 for the culture filtrate from 202-71 strains and 1.42 for the culture filtrate from the M50 strains (Table 1).
  • the 5L jar fermenter culture solution of strains M50 and 202-71 obtained in Example 2 was filtered through Nutsche with a filter aid (body mix), and then ion-exchanged resin ( Adsorbed to Amberlite IRC-50 (Na + type), manufactured by Rohm and Haas, 300 mL). After elution of colistin from the ion exchange resin with about 0.4 mol ZL sulfuric acid, wash it with 600 mL of deionized water, and concentrate the resulting eluent and washing solution mixture to a concentration of about 5% (W / V). Thus, a colistin-rich solution was obtained.
  • the absorbance at 400nm of the high colistin solution is 0.035 for the high colistin solution from 202-71, compared to 0.035 for the high colistin solution from the M50 strain, clearly from the M50 strain.
  • the coloration of the high colistin solution was light (Table 3).
  • each colistin-rich solution was spray-dried to obtain the desired colistin bulk powder.
  • the colistin powder derived from 202-71 has a brownish color.
  • the colistin powder derived from the M50 strain has a slightly yellowish white color, and the coloration of the colistin powder derived from the M50 strain is clearly lighter than that of the colistin powder derived from the 202-71 strain. It was white.
  • Each colistin powder was dissolved in deionized water to a concentration of 5% (WZV) to obtain a 5% concentration (WZV) aqueous solution.
  • Example 1 The liquid obtained by dissolving the M50 strain-derived colistin powder obtained in Example 3 in deionized water was analyzed by liquid chromatography (HPLC), and the results are shown in FIG.
  • HPLC liquid chromatography
  • Mobile phase 4. Dissolve 46 g of anhydrous sodium sulfate in 900 ml of pure water, add 2.5 ml of phosphoric acid, and make up to 100 ml (pH 2.3 to 2.5). This solution 78 is mixed with acetonitrile at a ratio of 22.
  • the liquid containing high colistin derived from 202-71 obtained in Example 3 was tested for the amount of decolorized carbon necessary to make the color tone of the liquid containing high colistin derived from M50 obtained in Example 3. .
  • a novel production strain useful in a method for producing colistin bulk powder can be provided. Furthermore, by using the strain of the present invention, it is possible to provide an efficient method for producing a colistin powder without going through the decoloring step, which is essential for the conventional method for producing a colistin powder.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Biophysics (AREA)
  • Biomedical Technology (AREA)
  • Microbiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

L'invention concerne un procédé de production d'une poudre de colistine en vrac effectué sans avoir recours à une étape de décoloration, grâce auquel les problèmes rencontrés dans les procédés de production existants (par exemple une durée de production très longue due à l'étape de décoloration, une augmentation du coût due à une baisse du rendement de production du composant colistine principal et une charge pour l'environnement provoquée par le dégagement d'un rejet carboné) peuvent être surmontés. L'invention concerne ainsi le microorganisme Bacillus polymyxa var. colistinus, lequel est un microorganisme capable de produire une poudre de colistine en vrac ayant une blancheur élevée; une poudre de colistine en vrac ayant une blancheur élevée; et un procédé de production d'une poudre de colistine en vrac ayant une blancheur élevée.
PCT/JP2006/316057 2006-08-15 2006-08-15 Procédé de production de poudre de colistine en vrac WO2008020474A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN200680028123XA CN101296938B (zh) 2006-08-15 2006-08-15 粘菌素原料粉末的制造方法
PCT/JP2006/316057 WO2008020474A1 (fr) 2006-08-15 2006-08-15 Procédé de production de poudre de colistine en vrac

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2006/316057 WO2008020474A1 (fr) 2006-08-15 2006-08-15 Procédé de production de poudre de colistine en vrac

Publications (1)

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WO2008020474A1 true WO2008020474A1 (fr) 2008-02-21

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CN (1) CN101296938B (fr)
WO (1) WO2008020474A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102102117B (zh) * 2010-11-17 2013-03-13 江苏大学 适用降血压肽工程菌的培养基

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5847493A (ja) * 1981-09-12 1983-03-19 Kyowa Hakko Kogyo Co Ltd コリスチンの製造法
JP2001505557A (ja) * 1996-11-15 2001-04-24 パソジェネシス コーポレイション 肺感染を処置するための、純粋な生物学的活性コリスチン、その成分、およびコリスチン処方物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1090459C (zh) * 1994-06-29 2002-09-11 明治制果株式会社 含有硫酸粘菌素的稳定组合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5847493A (ja) * 1981-09-12 1983-03-19 Kyowa Hakko Kogyo Co Ltd コリスチンの製造法
JP2001505557A (ja) * 1996-11-15 2001-04-24 パソジェネシス コーポレイション 肺感染を処置するための、純粋な生物学的活性コリスチン、その成分、およびコリスチン処方物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HIGNITE C.E. ET AL.: "Synthesis of theophylline-8-13C", J. LABELLED COMPD. RADIOPHARM., vol. 14, no. 3, 1978, pages 475 - 478, XP003021076 *
NAGASAKI I.: "Funmatsujo Kasseitan ni Kawaru Kenben na Hoho de aru Cuno-sha Zeta Carbon Filter no Tekio", NIPPON PDA NENKAI KOEN YOKOSHU (DAI 11 KAI), 2003, pages 65 - 70, XP003021077 *

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CN101296938B (zh) 2012-04-11
CN101296938A (zh) 2008-10-29

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