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WO2006111561A1 - Production amelioree d'anthracyclines d'origine microbienne - Google Patents

Production amelioree d'anthracyclines d'origine microbienne Download PDF

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Publication number
WO2006111561A1
WO2006111561A1 PCT/EP2006/061708 EP2006061708W WO2006111561A1 WO 2006111561 A1 WO2006111561 A1 WO 2006111561A1 EP 2006061708 W EP2006061708 W EP 2006061708W WO 2006111561 A1 WO2006111561 A1 WO 2006111561A1
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WIPO (PCT)
Prior art keywords
epirubicin
epidaunorubicin
cells
microbial
culture broth
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PCT/EP2006/061708
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English (en)
Inventor
Van Den Marco Alexander Berg
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DSM IP Assets BV
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DSM IP Assets BV
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Classifications

    • 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
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C12P19/56—Preparation of O-glycosides, e.g. glucosides having an oxygen atom of the saccharide radical directly bound to a condensed ring system having three or more carbocyclic rings, e.g. daunomycin, adriamycin
    • 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
    • C12R2001/465—Streptomyces

Definitions

  • the present invention relates to the fermentative production of epidaunorubicin and epirubicin in a host cell.
  • Anthracyclins are clinically important cancer chemotherapeutic agents.
  • Compounds belonging to this group are, amongst others, daunorubicin, doxorubicin and rhodomycin. Although these products are widely applied, the annual production is only several hundred kilograms due to the complex and expensive manufacturing routes. Besides this, there are several serious drawbacks such as undesirable acute and long- term toxic effects during clinical application, stressing the need for less toxic derivatives, with equal clinical effect and at lower cost.
  • epirubicin is very difficult to obtain due to low yields of the overall synthetic pathway.
  • Streptomyces peuceticus also referred to as Streptomyces peucetius
  • ATCC29050 as the preferred type strain
  • doxorubicin namely Streptomyces peuceticus subspecies caesius ATCC27952.
  • the latter is a mutant strain derived from the ATCC29050 strain and the relative low amount of doxorubicin is formed by C- 14 hydroxylation of its immediate precursor, daunorubicin.
  • Many efforts have been put in increasing the titers of final products and conversion ratio of daunorubicin into doxorubicin.
  • Current production strains have a daunorubicin titer over 1 g.l "1 but the complicated recovery process makes it a costly product.
  • Rhodomycin D CH 2 CH 3 H OH OH C(O)OCH 3
  • Doxorubicin can also be synthesized chemically starting from daunorubicin. This requires three steps with a yield of approximately 50%. The replacement of these three Chemical steps by a single enzymatic oxidation (doxA hydroxylase) is attractive, but this enzyme has very low in vivo activity. There is quite some engineering needed to increase the fluxes in Streptomyces peuceticus towards increased doxorubicin production (J. Bacteriol. (1999) 181, 305-318; J. Bacteriol. (1996) 178, 7316-7321 ). In US 5,695,966, the use of the DNA fragment encoding such an enzyme in other species is described, but also here the yields remain low.
  • the drawbacks of the second method are that the yields of epirubicin and its precursor epidaunorubicin are so low compared to the other anthracyclins produced that industrial application is not feasible.
  • Low productivities for epidaunorubicin up to 0.065 g.r 1 were reported (Nat. Biotechnol. (1998) 16, 69-74), and although the production of epirubicin was indeed detected, the overall productivity of this compound was still lower than that of epidaunorubicin.
  • a method by which these unfavorable yields could be improved, or strains displaying economically feasible levels of epidaunorubicin and/or epirubicin productivity have not been reported. Therefore, an economically feasible way of producing epirubicin and epidaunorubicin as pure compounds is not available and is extremely desirable.
  • microbial strains with the desired improved productivity can be obtained by incubating a population of microbial cells, selecting a subpopulation of viable cells, and isolating cells out of the subpopulation of cells that produce at least 0.1 g.l "1 culture broth of epidaunorubicin and/or epirubicin.
  • the present invention provides a microbial strain that produces at least 0.1 g.l "1 culture broth of epidaunorubicin and/or epirubicin and a method to obtain said microbial strain comprising plating out a population of microbial cells, selecting a subpopulation of viable cells, and isolating cells out of the subpopulation of cells that produce at least 0.1 g.l "1 culture broth of epidaunorubicin and/or epirubicin.
  • the present invention provides a method for the production of epidaunorubicin and/or epirubicin comprising fermentation of a microbial strain that produces at least 0.1 g.l "1 culture broth of epidaunorubicin and/or epirubicin under conditions conducive to the production of epidaunorubicin and/or epirubicin.
  • a microbial strain in particular an actinomycete strain, that produces at least 0.1 g.l "1 culture broth of an ⁇ -L-arabino-hexopyranoside-derived anthracyclin like epidaunorubicin or epirubicin.
  • the actinomycete strain of the invention produces at least 1 g.l "1 culture broth of an ⁇ -L-arabino-hexopyranoside-derived anthracyclin, more preferably at least 10 g.l "1 culture broth.
  • an upper limit in anthracyclin titers may be around 50-70 g.l "1 , although this may be further increased by in situ product removal.
  • the production levels are given in yields: at least 5 mg.g "1 biomass dry-weight, more preferably at least 50 mg.g "1 biomass dry- weight and most preferably at least 500 mg.g "1 biomass dry-weight of an ⁇ -L-arabino-hexopyranoside derived anthracyclin.
  • the microbial strain is from the genus Streptomyces, such as Streptomyces peuceticus.
  • the ratio of the sum of both epidaunorubicin and epirubicin over the sum of all other anthracyclins present, like daunorubicin, doxorubicin and rhodomycin D is higher than 0.1 , more preferably higher than 1 , even more preferably higher than 10 and most preferably higher than 100.
  • the ratio of epirubicin over epidaunorubicin is higher than 0.01 , preferably higher than 0.1 , more preferably higher than 1 , even more preferably higher than 10 and most preferably higher than 100.
  • the microbial strain of the present invention can be obtained by incubating a population of microbial cells, selecting a subpopulation of viable cells, and isolating cells out of the subpopulation of cells that produce at least 0.1 g.l "1 culture broth of epidaunorubicin and/or epirubicin.
  • the population of microbial cells already produces epidaunorubicin and/or epirubicin, albeit at low concentrations, i.e. ranging from 0.005 g.l "1 to 0.075 g.l "1 culture broth.
  • An example of such microbial cells are the genetically engineered strains of Streptomyces peuceticus described by Madduri etal. (Nat. Biotechnol.
  • epidaunorubicin and/or epirubicin producing microbial cells can be obtained by isolating the anthracyclin metabolic pathway structural genes in the form of synthetic DNA, which is in vitro adapted for producing epidaunorubicin and/or epirubicin.
  • the method described above is also suitable to convert a microbial strain that produces at least 0.075 g.l "1 culture broth of epidaunorubicin and/or epirubicin into a strain that produces more epidaunorubicin and/or epirubicin and/or in a different ratio than the starting strain.
  • the said population of microbial cells may be incubated in the presence of a suitable toxin and the said subpopulation of cells is isolated (selected) as being resistant against said toxin.
  • the toxin that is applied should be toxic to the starting population of microbial cells, i.e. the toxin should have the effect that the cells are unable to grow or to survive when incubated in the presence of a suitable concentration of the toxin.
  • a subpopulation of the cells is isolated that displays resistance to the toxin, i.e. is able to grow in the presence of the toxin.
  • a subset of these toxin-resistant cells may have obtained one or more mutations providing, for instance, an improved production level of the anthracyclins epidaunorubicin and/or epirubicin.
  • resistant cells might be non-sensitive anthracyclin overproducing cells
  • resistant cells might be cells that produce an altered level and/or composition of anthracyclins; - Precursors like fluoropropionate, which becomes toxic to the cells upon consumption as carbon source for growth, resistant cells might be cells that have an increased flux through the anthracyclin biosynthetic pathway due to a decreased co-consumption of the common substrate, propionate;
  • resistant cells might be cells that have an increased flux through the anthracyclin pathway irrespective of the main carbon source used.
  • a suitable concentration of the toxin typically lies around the minimal inhibitory concentration (MIC value) found for the microbial cells that are subjected to the method of the invention.
  • the MIC value will be dependent on the microbial cells that are used and may be between for instance 0.001 and 10 g. I "1 .
  • microbial strains are isolated that produce at least 0.1 g.l "1 culture broth of the anthracyclins epidaunorubicin and/or epirubicin.
  • a high percentage of toxin-resistant cells produce at least 0.1 g.l "1 culture broth of the anthracyclins epidaunorubicin and/or epirubicin.
  • the population of microbial cells that is subjected to the method of the invention may be a population of identical cells derived from one particular parent strain. In this way, typically spontaneous mutants may be isolated.
  • the population of microbial cells that is subjected to the method of the invention may also be a population of cells that is firstly subjected to a mutagenic treatment to deliberately introduce genetic variation into said population.
  • the mutagenic treatment typically may comprise a so-called classical treatment, but also may include DNA-mediated transformation.
  • a classical treatment includes protoplast fusion and/or a treatment with UV radiation or certain chemicals.
  • adaptive evolution techniques maybe used to isolate cells that produce at least 0.1 g.l "1 culture broth of anthracyclins epidaunorubicin and/or epirubicin.
  • the said subpopulation of cells with or without prior mutagenic treatment, will be cultivated in sub- selective conditions, which are conditions were the level of toxin applied is just below or around the determined MIC value.
  • Subsequent dilutions of the culture broth in fresh media and slowly increased levels of the toxin will stimulate the gradual selection and increase of the said subpopulation of cells for with an improved production level or, alternatively, an altered ratio of the anthracyclins epidaunorubicin and/or epirubicin.
  • Such adaptive evolution experiments can also be performed by using selective cultivation conditions, like for example a changed temperature, an increased stirrer speed, an altered pH or a difficult to consume carbon source, under which the parent cells do not grow or at least show very poor growth, while the said subpopulation of cells for with an improved production level of the anthracyclins have an evolutionary advantage and start to accumulate.
  • this technique can be used to find the very rare cells with the aimed characteristics.
  • the mutagenic treatment is done on toxin-resistant cells, preferably on toxin-resistant cells that produce at least 0.1 g.l "1 culture broth of the anthracyclins epidaunorubicin and/or epirubicin.
  • microbial strains are isolated that display, as compared to a parent strain, an improved productivity of the anthracyclins epidaunorubicin and/or epirubicin and/or a change in the ratio of the different anthracyclins produced.
  • a parent strain is a strain that does not substantially produce the anthracyclins epidaunorubicin and/or epirubicin.
  • a suitable parent strain may be a strain that produces epidaunorubicin and/or epirubicin at a level that is lower than 0.1 g.l "1 culture broth.
  • Typical examples of such parent strains are disclosed by Madduri etal. (Nat. Biotechnol. (1998) 16, 69-74).
  • the person skilled in the art will know that further improvement of the anthracyclin titers produced by the strains of the present invention can be obtained by transforming the cells that produce 0.1 g.l "1 culture broth or more of anthracyclins with polynucleotides affecting the anthracyclin biosynthesis pathway.
  • These can be isolated from known anthracyclin producing species like, but not limited to, Streptomyces and
  • Saccharopolyspora Preferred examples are Streptomyces peuceticus, Streptomyces peuceticus subspecies caesius, Streptomyces insignis, Streptomyces avermitilis and Saccharopolyspora erythraea. These can be genes encoding enzymes of (related) pathways, transcription factors regulation expression levels of the biosynthetic pathway, additional copies of the gene cluster encoding the biosynthetic pathway, but also anti- sense polynucleotides can be used to hamper competition metabolic pathways.
  • a method for the production of epidaunorubicin and/or epirubicin comprising fermentation of the microbial strain of the first aspect of the invention under conditions conducive to the production of epidaunorubicin and/or epirubicin.
  • the cells according to the invention may be cultured using procedures known in the art. Of course many procedures are available to the skilled person and many variations within these procedures are possible. As a non-limiting example, reference is made to a suitable procedure as reported by Lomovskaya etal. (J. Bacteriol. (1999) 181, 305-318). After fermentation, if necessary, the cells can be removed from the fermentation broth by means of centrifugation or filtration. The anthracyclins epidaunorubicin and/or epirubicin may then be recovered and, if desired, purified and isolated by conventional means. Said means include crystallization, chromatographic procedures, extraction techniques and the like.
  • the anthracyclins may be produced in a two-step process.
  • daunorubicin and/or, more preferably, doxorubicin may be produced fermentative by an optimized cell, which may be converted in a second step to epidaunorubicin and/or epirubicin by a second cell, which is equipped to do so.
  • the seed culture is transferred to 25 ml of the APM production medium containing glucose (60 g.l “1 ), yeast extract (8 g.l “1 ), malt extract (20 g.l “1 ), NaCI (2 g.l “1 ), MOPS sodium salt (15 g.l “1 ), MgSO 4 (0.1 g.l “1 ), FeSO 4 * 7HO (0.01 g.l “1 ), ZnSO 4 * 7HO (0.01 g.l “1 ), and antifoam B emulsion (4 ml; Sigma) and incubated in a 250-ml baffled flask as described above for 72 h.
  • Cultures are extracted with chloroform and analyzed by high-performance liquid chromatography (HPLC).
  • HPLC high-performance liquid chromatography
  • Example 2 Epidaunorubicin and epirubicin formation
  • the isolates obtained as described in example 1 were cultivated as follows. Five ml of seed medium containing glucose (25 g.l “1 ), yeast extract (4 g.l “1 ), malt extract (10 g.
  • the seed culture is transferred to 25 ml of the APM production medium containing glucose (60 g.l “1 ), yeast extract (8 g.l “1 ), malt extract (20 g.l “1 ), NaCI (2 g.l “1 ), MOPS sodium salt (15 g.l “1 ), MgSO 4 (0.1 g.l “1 ), FeSO 4 * 7HO (0.01 g.l “1 ), ZnSO 4 * 7HO (0.01 g.l “1 ), and antifoam B emulsion (4 ml; Sigma) and incubated in a 250-ml baffled flask as described above for 72 h.

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  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Wood Science & Technology (AREA)
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  • General Engineering & Computer Science (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
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  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Souche microbienne produisant au moins 0.1 g.l-1 de bouillon de culture d'épidaunorubicine et/ou d'épirubicine. De préférence, la souche provient de l'espèce Strptomyces. Procédé de production d'épidaunorubicine et/ou d'épirubicine par fermentation de la souche considérée dans des conditions qui se prêtent à ladite production.
PCT/EP2006/061708 2005-04-21 2006-04-20 Production amelioree d'anthracyclines d'origine microbienne Ceased WO2006111561A1 (fr)

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EP05103220.9 2005-04-21
EP05103220 2005-04-21

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1990405A1 (fr) 2007-05-08 2008-11-12 W. C. Heraeus GmbH Souches modifiées génétiquement produisant des métabolites anthracyclines utiles en tant que médicaments contre le cancer
WO2009035107A1 (fr) 2007-09-14 2009-03-19 Meiji Seika Kaisha, Ltd. Procédé de production d'un antibiotique non naturel
WO2010028667A1 (fr) * 2008-09-11 2010-03-18 W.C. Heraeus Gmbh Souches génétiquement modifiées pour des biotransformations dans la fabrication d'anthracyclines
JP2010252657A (ja) * 2009-04-22 2010-11-11 Meiji Seika Kaisha Ltd ケトレダクターゼ変異体
WO2011145211A1 (fr) 2010-05-21 2011-11-24 明治製菓株式会社 Mutant de cétone réductase
WO2013001862A1 (fr) * 2011-06-29 2013-01-03 雪印種苗株式会社 Bactérie lactique inédite et procédé de préparation de produits d'ensilage ou d'aliments fermentés l'utilisant
CN106282042A (zh) * 2015-05-15 2017-01-04 浙江海正药业股份有限公司 一种波赛链霉菌及其生产表柔红霉素的方法

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4345068A (en) * 1979-11-22 1982-08-17 Farmitalia Carlo Erba S.P.A. Process for the preparation of 4'-epidaunorubicin, 3',4'-diepidaunorubicin, their doxorubicin analogs, and intermediates used in said process
DE3309849A1 (de) * 1982-03-20 1983-09-22 Farmitalia Carlo Erba S.p.A., 20159 Milano Mikrobiologisches verfahren fuer die herstellung eines anthracyclin-antibiotikums, das bei diesem verfahren erhaltene antibiotikum und eine pharmazeutische zubereitung
JPS60186298A (ja) * 1984-02-27 1985-09-21 Sanraku Inc アドリアマイシンの製造法
DD251574A1 (de) * 1986-07-31 1987-11-18 Adw Ddr Verfahren zur herstellung von aklanonsaeure
WO1996027014A1 (fr) * 1995-02-27 1996-09-06 Pharmacia S.P.A. Procede de preparation de la doxorubicine
EP0848009A1 (fr) * 1996-12-16 1998-06-17 Pharmachemie B.V. Procédé pour la préparation d'épirubicin ou leurs sels d'addition en commençant avec du daunorubicin
WO1999055829A2 (fr) * 1998-04-24 1999-11-04 Pharmacia & Upjohn S.P.A. Procede de preparation de doxorubicine
WO2003057687A1 (fr) * 2001-12-27 2003-07-17 Albany Molecular Research, Inc. Procedes permettant de preparer des derives de doxorubicine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4345068A (en) * 1979-11-22 1982-08-17 Farmitalia Carlo Erba S.P.A. Process for the preparation of 4'-epidaunorubicin, 3',4'-diepidaunorubicin, their doxorubicin analogs, and intermediates used in said process
DE3309849A1 (de) * 1982-03-20 1983-09-22 Farmitalia Carlo Erba S.p.A., 20159 Milano Mikrobiologisches verfahren fuer die herstellung eines anthracyclin-antibiotikums, das bei diesem verfahren erhaltene antibiotikum und eine pharmazeutische zubereitung
JPS60186298A (ja) * 1984-02-27 1985-09-21 Sanraku Inc アドリアマイシンの製造法
DD251574A1 (de) * 1986-07-31 1987-11-18 Adw Ddr Verfahren zur herstellung von aklanonsaeure
WO1996027014A1 (fr) * 1995-02-27 1996-09-06 Pharmacia S.P.A. Procede de preparation de la doxorubicine
EP0848009A1 (fr) * 1996-12-16 1998-06-17 Pharmachemie B.V. Procédé pour la préparation d'épirubicin ou leurs sels d'addition en commençant avec du daunorubicin
WO1999055829A2 (fr) * 1998-04-24 1999-11-04 Pharmacia & Upjohn S.P.A. Procede de preparation de doxorubicine
WO2003057687A1 (fr) * 2001-12-27 2003-07-17 Albany Molecular Research, Inc. Procedes permettant de preparer des derives de doxorubicine

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ARCAMONE F ET AL: "Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius", BIOTECHNOLOGY AND BIOENGINEERING, vol. 11, no. 6, 1 November 1969 (1969-11-01), pages 1101 - 1110, XP000571944, ISSN: 0006-3592 *
DATABASE WPI Section Ch Week 198544, Derwent World Patents Index; Class B03, AN 1985-273653, XP002342897 *
HUTCHINSON C R ET AL: "Genetic engineering of doxorubicin production in Streptomyces peucetius: A review", JOURNAL OF INDUSTRIAL MICROBIOLOGY AND BIOTECHNOLOGY, vol. 23, no. 1, July 1999 (1999-07-01), pages 647 - 652, XP002342779, ISSN: 1367-5435 *
LAL R ET AL: "Engineering antibiotic producers to overcome the limitations of classical strain improvement programs", CRITICAL REVIEWS IN MICROBIOLOGY, vol. 22, no. 4, 1996, pages 201 - 255, XP002044016 *
LOMOVSKAYA N ET AL: "Doxorubicin overproduction in Streptomyces peucetius: Cloning and characterization of the dnrU ketoreductase and dnrV genes and the doxA cytochrome P-450 hydroxylase gene", JOURNAL OF BACTERIOLOGY, vol. 181, no. 1, January 1999 (1999-01-01), pages 305 - 318, XP002342780, ISSN: 0021-9193 *
MADDURI K ET AL: "Production of the antitumor drug epirubicin (4'-epidoxorubicin) and its precursor by a genetically engineered strain of Streptomyces peucetius", NATURE BIOTECHNOLOGY, vol. 16, no. 1, January 1998 (1998-01-01), pages 69 - 74, XP002210929, ISSN: 1087-0156 *
SALAS J A ET AL: "Genetic manipulation of antitumor-agent biosynthesis to produce novel drugs", TRENDS IN BIOTECHNOLOGY, vol. 16, no. 11, 1 November 1998 (1998-11-01), pages 475 - 482, XP004139981, ISSN: 0167-7799 *
SCOTTI C ET AL: "Enhanced antibiotic production by manipulation of the Streptomyces peucetius dnrH and dnmT genes involved in doxorubicin (adriamycin) biosynthesis", JOURNAL OF BACTERIOLOGY, vol. 178, no. 24, December 1996 (1996-12-01), pages 7316 - 7321, XP002067136, ISSN: 0021-9193 *

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WO2008135195A1 (fr) * 2007-05-08 2008-11-13 W.C. Heraeus Gmbh Souches génétiquement modifiées produisant des métabolites d'anthracycline utiles en tant que médicaments contre le cancer
JP2010525828A (ja) * 2007-05-08 2010-07-29 ヴェー ツェー ヘレーウス ゲゼルシャフト ミット ベシュレンクテル ハフツング 癌薬剤として使用できるアンスラサイクリン代謝産物を産生する遺伝子改変株
KR101177175B1 (ko) 2007-05-08 2012-08-24 헤레우스 프레셔스 메탈스 게엠베하 운트 코. 카게 항암제로 유용한 안트라사이클린 대사산물을 생산하는 유전자 변형 균주
EP1990405A1 (fr) 2007-05-08 2008-11-12 W. C. Heraeus GmbH Souches modifiées génétiquement produisant des métabolites anthracyclines utiles en tant que médicaments contre le cancer
CN101802168B (zh) * 2007-09-14 2013-06-12 明治制果株式会社 非天然型抗生素的制造方法
WO2009035107A1 (fr) 2007-09-14 2009-03-19 Meiji Seika Kaisha, Ltd. Procédé de production d'un antibiotique non naturel
JP5422387B2 (ja) * 2007-09-14 2014-02-19 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 非天然型抗生物質の製造方法
US8383392B2 (en) 2007-09-14 2013-02-26 Meiji Seika Pharma Co., Ltd. Transformant and method for production of non-natural antibiotic
WO2010028667A1 (fr) * 2008-09-11 2010-03-18 W.C. Heraeus Gmbh Souches génétiquement modifiées pour des biotransformations dans la fabrication d'anthracyclines
AU2008361598B2 (en) * 2008-09-11 2015-02-12 Heraeus Precious Metals Gmbh & Co Kg Genetically modified strains for biotransformations in anthracycline production
JP2012501663A (ja) * 2008-09-11 2012-01-26 ヴェー・ツェー・ヘレウス・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング・ウント・コンパニー・コマンディット・ゲゼルシャフト アントラサイクリン産生における生体内変換のための遺伝子組み換え菌株
JP2010252657A (ja) * 2009-04-22 2010-11-11 Meiji Seika Kaisha Ltd ケトレダクターゼ変異体
CN102906258A (zh) * 2010-05-21 2013-01-30 明治制果药业株式会社 酮还原酶突变体
KR20130090774A (ko) 2010-05-21 2013-08-14 메이지 세이카 파루마 가부시키가이샤 케토리덕타아제 변이체
US8697409B2 (en) 2010-05-21 2014-04-15 Meiji Seika Pharma Co., Ltd. Ketoreductase mutant
WO2011145211A1 (fr) 2010-05-21 2011-11-24 明治製菓株式会社 Mutant de cétone réductase
CN102906258B (zh) * 2010-05-21 2015-06-17 明治制果药业株式会社 酮还原酶突变体
WO2013001862A1 (fr) * 2011-06-29 2013-01-03 雪印種苗株式会社 Bactérie lactique inédite et procédé de préparation de produits d'ensilage ou d'aliments fermentés l'utilisant
JPWO2013001862A1 (ja) * 2011-06-29 2015-02-23 雪印種苗株式会社 新規乳酸菌及びこれを用いるサイレージ又は発酵飼料の調製方法
CN106282042A (zh) * 2015-05-15 2017-01-04 浙江海正药业股份有限公司 一种波赛链霉菌及其生产表柔红霉素的方法
CN106282042B (zh) * 2015-05-15 2019-12-10 浙江海正药业股份有限公司 一种波赛链霉菌及其生产表柔红霉素的方法

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