WO2005095591A2 - Nouveaux genes provenant d'une batterie de genes de biosynthese, pour la synthese d'antibiotiques aminoglycosides, et nouveaux antibiotiques aminoglycosides ainsi obtenus - Google Patents
Nouveaux genes provenant d'une batterie de genes de biosynthese, pour la synthese d'antibiotiques aminoglycosides, et nouveaux antibiotiques aminoglycosides ainsi obtenus Download PDFInfo
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- WO2005095591A2 WO2005095591A2 PCT/DE2005/000499 DE2005000499W WO2005095591A2 WO 2005095591 A2 WO2005095591 A2 WO 2005095591A2 DE 2005000499 W DE2005000499 W DE 2005000499W WO 2005095591 A2 WO2005095591 A2 WO 2005095591A2
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- aminoglycoside
- streptom
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- nucleic acid
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Classifications
-
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/52—Genes encoding for enzymes or proenzymes
Definitions
- the invention relates to new genes from aminoglycoside-producing microorganisms, new gene clusters which are formed from new and / or known genes of these microorganisms, expression products of these genes, transformation vehicles containing such genes or gene clusters, transformed cells containing such genes or gene clusters, processes for biotechnological production of aminoglycosides, processes for combinatorial biosynthesis of argininoglycoside derivatives, new aminoglycosides, uses of such aminoglycosides and pharmaceutical compositions containing such aminoglycosides.
- Aminoglycoside antibiotics are substances that kill gram-positive and gram-negative bacteria by interfering with protein synthesis (binding to 30s subunits of the bacterial ribosomes and inhibiting translation or blocking the formation of correct peptide bonds between amino acids). E. coli and Klebsieila in particular may be mentioned as examples of target bacteria. Multi-resistant pathogen strains can also be detected using aminoglycoside antibiotics, which is why aminoglycoside antibiotics are particularly useful as reserve antibiotics for patients with life-threatening infections Find use. This is also indicated by the fact that cross-resistance to other antibiotic groups is rare.
- biosynthesized aminoglycosides are secondary etabolites of the microorganisms used for the synthesis.
- the enzymes or enzyme groups relevant for the synthesis are expressed by the genes or gene clusters of the microorganisms.
- the combination of such genes or gene clusters ultimately determines the specific structure of the aminoglycoside produced.
- these new derivatives of the naturally produced aminoglycosides can be produced.
- genes and / or gene clusters a large number of different derivatives can be generated, which in turn can be tested for effectiveness, in particular increased activity compared to known aminoglycosides, and / or reduced side effects in screening processes.
- the invention is therefore based on the technical problem, means for creating new aminoglycosides, in particular with an improved effect and / or reduced side effects.
- the invention teaches an isolated protein or peptide containing, in particular consisting of, one of the disclosed amino acid sequences.
- Proteins or peptides according to the invention can be expressed in a cell for biosynthesis, but it is also possible to import externally generated protein or peptides into a cell carrying out the biosynthesis.
- the protein or peptide is preferably for a partial synthesis step of the biosynthesis of an aminoglycoside, in particular an aminoglycoside antibiotic, for example selected from the group consisting of "butirosins, gentamicins, neomycins, fortimicins, tobramycin, apramycin, paromomycin, hygromycin B, ribostamycin , Sagamicine, Sisomicine, Kana ycine, Nebramycine, Seldo ycine, Destomycine, Istamycine, Sannamycine, Dacti icine, Sporaricine, Bluensomycine, Ashimycine, Lividomyeine and Spectino ycine "functional.
- an aminoglycoside antibiotic for example selected from the group consisting of "butirosins, gentamicins, neomycins, fortimicins, tobramycin, apramycin, paromomycin, hygromycin
- the invention further relates to an isolated nucleic acid, in particular DNA, for example genomic DNA, or RNA, in particular mRNA, coding for a protein or peptide according to the invention.
- the invention further comprises an isolated transformation vehicle, in particular a plasmid or cosmid, containing a nucleic acid according to the invention.
- a transformation vehicle in particular a plasmid or cosmid
- the transformation vehicle can additionally contain at least one regulatory nucleic acid sequence, the nucleic acid being under the control of the regulatory nucleic acid sequence, in particular a promoter.
- one or more regulatory sequences can be set up with the proviso that a plurality of nucleic acids, in particular a gene cluster or part of a gene cluster, are controlled.
- Suitable cells are preferably selected from the group consisting of "Bacillus circulans, in particular NRRL B3312, Micromonospora echinosporea, in particular DSM 43036, Streptom. Kana yceticus, in particular DSM 40500, Streptom. Fradiae, in particular DSM 2458, Micromonospora olicasterspora, in particular DSM 43868, Streptom . tenbrarius, in particular DSM 40477, Streptom. rimosus ssp. paromomycinus, in particular ATCC 2455, Streprom. hygroscopicus ssp. hygroscopicus, in particular DSM 40578, Streprom.
- ribosidificus in particular ATCC 21294, Micromonospora spec., in particular DSM 439pora inyoensis, in particular NRRL 3292, Streptoaloteichus hindustanus, in particular DSM 44523, Streptom. hofunensis sp. nov, Streptom. rimofaciens, in particular ATCC 21066, Streptom. ten imariensis, in particular ATCC 31603, Streptom.
- sannaensis in particular IFO 14239, Dacium tylospor matsuzakiense, in particular DSM 43810, Saccharopolyspora hirsuta, in particular ATCC 20501, St reptom. griseus N2-3-11, especially ATCC 23345, streptom. glaucescens GLA.O, especially ETH 22794, streptom. blu- ensis, especially DSM 40564, streptom. griseus FT3-4, streptom. flavopersicus, particularly NRLL 2820 A.
- Table I summarizes the antibiotics that can be produced by these strains.
- one the cell according to the invention is a mutant of the above strains generated with a transformation vehicle according to the invention and that the antibiotic which can be produced therewith is derivatized.
- the invention also includes aminoglycosides, in particular aminoglycoside antibiotics, which can be obtained by cultivating a cell according to the invention and, after cultivation, isolating the aminoglycoside from the cell and / or from the culture supernatant.
- An aminoglycoside according to the invention is suitable for producing a pharmaceutical composition for the treatment of bacterial or viral infections, in particular infections with gram-negative bacteria, for example with E. coli or Klebsiella. The biosynthesis can be mutated in such a way that the new
- Aminoglycoside antibiotic has an improved effectiveness over known active ingredients. However, it is also possible for an amine ⁇ glycoside antibiotic according to the invention to be used “only” as a replacement therapy for resistance to a known active ingredient. The advantage then lies in the fact that therapy is only possible again using the active substance according to the invention. However, new aminoglycoside antibiotics with reduced side effects are also particularly desirable.
- the invention further relates to a pharmaceutical composition containing an aminoglycoside according to the invention or several such aminoglycosides in a physiologically effective dose. It can also contain pharmaceutical auxiliaries and / or carriers.
- the pharmaceutical preparation of a pharmaceutical composition according to the invention can be carried out in a manner customary in the art. Counterions for ionic compounds are, for example Na + , K + , Li + or cyclohexylammonium in question.
- Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (IV, IP, IM, SC) or nebulization (Aerosols), transdermal systems, as well as preparations with protracted release of active substances, in the manufacture of which conventional auxiliaries such as carriers, explosives, binders, coating agents, swelling agents, lubricants or lubricants, flavors, sweeteners and solubilizers are used.
- auxiliaries such as carriers, explosives, binders, coating agents, swelling agents, lubricants or lubricants, flavors, sweeteners and solubilizers are used.
- a pharmaceutical composition of the invention is producible, that at least one active ingredient used according to the invention is mixed in a defined dose with a pharmaceutically suitable and physiologically tolerated carrier and possibly further suitable active compounds, additives or auxiliaries with a defined 'inhibitor dose and prepared into the desired presentation.
- a pharmaceutical composition according to the invention is preferably galenically prepared for oral or parenteral administration.
- Example 1 Butirosin Cluster List 1 describes amino acid sequences of the butirosin biosynthesis gene cluster, including the functions of the individual genes.
- Gentamicin Cluster List 2 describes amino acid sequences of the gentamicin biosynthesis gene cluster, including the functions of the individual genes.
- Kanamycin Cluster List 3 describes amino acid sequences of the kanamycin biosynthesis gene cluster, including the functions of the individual genes.
- Neomycin Cluster List 4 describes amino acid sequences of the Neumycin biosynthesis gene cluster, including the functions of the individual genes.
- Example 5 Fortimicin Cluster List 5 describes amino acid sequences of the fortimicin biosynthesis gene cluster, including the functions of the individual genes.
- Example 6 Tobramycin / Apramycin Cluster Lists 6 and 12 describe amino acid sequences of the tobramycin / apramycin biosynthesis gene cluster, including the functions of the individual genes.
- Example 7 Paromomycin Cluster Lists 7 and 11 describe amino acid sequences of the paromomycin biosynthesis gene cluster, including the functions of the individual genes.
- Hygromycin B Cluster List 8 describes amino acid sequences of the hygromycin B biosynthesis gene cluster, including the functions of the individual genes.
- Example 9 Ribostamycin Cluster List 9 describes amino acid sequences of the ribostamycin biosynthesis gene cluster, including the functions of the individual genes.
- Lividomycin Cluster List 10 describes amino acid sequences of the lividomycin biosynthesis gene cluster, including the functions of the individual genes.
- Example 11 Istamycin Cluster List 13 describes amino acid sequences of the istamycin biosynthesis gene cluster, including the functions of the individual genes.
- Example 12 Apramycin Cluster List 14 describes amino acid sequences of the apramycin biosynthesis gene cluster, including the functions of the individual genes. Table I
- Micromonospora M.
- DSM 43036 Gentamicin echinospora M. spec.
- DSM 43912 Sagamicin M. inyoensis NRRL 3292 Sisomicin
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Abstract
L'invention concerne de nouveaux gènes provenant de micro-organismes produisant des aminoglycosides, de nouvelles batteries de gènes formées à partir de gènes nouveaux et/ou connus de ces micro-organismes, des produits d'expression de ces gènes, des véhicules de transformation renfermant de tels gènes ou de telles batteries de gènes, des cellules transformées renfermant de tels gènes ou de telles batteries de gènes. L'invention concerne en outre des procédés de production biotechnologique d'aminoglycosides, des procédés de biosynthèse combinatoire de dérivés d'aminoglycosides, de nouveaux aminoglycosides, des utilisations de tels aminoglycosides, ainsi que des compositions pharmaceutiques renfermant de tels aminoglycosides.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE200410017141 DE102004017141A1 (de) | 2004-04-01 | 2004-04-01 | Neue Gene aus Biosynthese Genclustern zur Synthese von Aminoglycosid-Antibiotika sowie damit herstellbare neue Aminoglycosid-Antibiotika |
| DE102004017141.6 | 2004-04-01 |
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| Publication Number | Publication Date |
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| WO2005095591A2 true WO2005095591A2 (fr) | 2005-10-13 |
| WO2005095591A3 WO2005095591A3 (fr) | 2006-07-20 |
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| PCT/DE2005/000499 WO2005095591A2 (fr) | 2004-04-01 | 2005-03-15 | Nouveaux genes provenant d'une batterie de genes de biosynthese, pour la synthese d'antibiotiques aminoglycosides, et nouveaux antibiotiques aminoglycosides ainsi obtenus |
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| DE (1) | DE102004017141A1 (fr) |
| WO (1) | WO2005095591A2 (fr) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009058679A1 (fr) * | 2007-10-30 | 2009-05-07 | Danisco Us Inc., Genencor Division | Protéase de streptomyces |
| EP2298879A1 (fr) * | 2008-06-05 | 2011-03-23 | Meiji Seika Kaisha, Ltd. | Procédé d'amplification de l'adn dans une cellule |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0035770A2 (fr) * | 1980-03-07 | 1981-09-16 | INTERx RESEARCH CORPORATION | Formulation médicamenteuse contenant un antibiotique glycosidique et un adjuvant |
| EP0204549A2 (fr) * | 1985-06-07 | 1986-12-10 | Eli Lilly And Company | Procédé d'isolement des gènes de biosynthèse d'antibiotiques |
Family Cites Families (1)
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| KR20030082708A (ko) * | 2002-04-18 | 2003-10-23 | 주식회사 바이오홀딩스 | 블루엔소마이신 생합성 효소의 유전자 염기서열 및 아미노산 서열과 그 형질전환체 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0035770A2 (fr) * | 1980-03-07 | 1981-09-16 | INTERx RESEARCH CORPORATION | Formulation médicamenteuse contenant un antibiotique glycosidique et un adjuvant |
| EP0204549A2 (fr) * | 1985-06-07 | 1986-12-10 | Eli Lilly And Company | Procédé d'isolement des gènes de biosynthèse d'antibiotiques |
Non-Patent Citations (13)
| Title |
|---|
| BEYER STEFAN ET AL: "The StrQ protein encoded in the gene cluster for 5'-hydroxystreptomycin of Streptomyces glaucescens GLA.0 is a alpha-D-glucose-1-phosphate cytidylyltransferase (CDP-D-glucose synthase)" EUROPEAN JOURNAL OF BIOCHEMISTRY, Bd. 258, Nr. 3, Dezember 1998 (1998-12), Seiten 1059-1067, XP002349933 ISSN: 0014-2956 * |
| DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; Mai 2001 (2001-05), LI T B ET AL: "ÄCloning of the sugar related biosynthesis gene cluster from Streptomyces tenebrarius H6]" XP002349939 Database accession no. NLM11517612 & SHENG WU GONG CHENG XUE BAO = CHINESE JOURNAL OF BIOTECHNOLOGY. MAY 2001, Bd. 17, Nr. 3, Mai 2001 (2001-05), Seiten 329-331, ISSN: 1000-3061 * |
| DATABASE NCBI SEQUENCE DATABASE 12. Juli 2005 (2005-07-12), TADASHI EGUCHI: "Bacillus butirosin-biosynthetic gene cluster complete and partial cds." XP002349940 gefunden im GENEBANK Database accession no. AB097196 * |
| DATABASE WPI Section Ch, Week 200417 Derwent Publications Ltd., London, GB; Class B03, AN 2004-176937 XP002349787 & KR 2003 082 708 A (null) 23. Oktober 2003 (2003-10-23) * |
| HASKELL T H ET AL: "The preparation and biological activity of novel amino acid analogs of butirosin." CARBOHYDRATE RESEARCH. JUN 1973, Bd. 28, Nr. 2, Juni 1973 (1973-06), Seiten 263-280, XP002082628 ISSN: 0008-6215 * |
| IKENO SOUICHI ET AL: "kasT gene of Streptomyces kasugaensis M338-M1 encodes a DNA-binding protein which binds to intergenic region of kasU-kasJ in the kasugamycin biosynthesis gene cluster." THE JOURNAL OF ANTIBIOTICS. DEC 2002, Bd. 55, Nr. 12, Dezember 2002 (2002-12), Seiten 1053-1062, XP008054360 ISSN: 0021-8820 * |
| JUNG YONG GYUN ET AL: "Isolation and characterization of bluensomycin biosynthetic genes from Streptomyces bluensis." FEMS MICROBIOLOGY LETTERS. 28 FEB 2003, Bd. 219, Nr. 2, 28. Februar 2003 (2003-02-28), Seiten 285-289, XP002349778 ISSN: 0378-1097 * |
| KHAREL MADAN KUMAR ET AL: "An approach for cloning biosynthetic genes of 2-deoxystreptamine-containing aminocyclitol antibiotics: isolation of a biosynthetic gene cluster of tobramycin from Streptomyces tenebrarius." BIOTECHNOLOGY LETTERS. DEC 2003, Bd. 25, Nr. 24, Dezember 2003 (2003-12), Seiten 2041-2047, XP002349777 ISSN: 0141-5492 * |
| LYUTZKANOVA DIMITRINA ET AL: "A spectinomycin resistance determinant from the spectinomycin producer Streptomyces flavopersicus" MICROBIOLOGY (READING), Bd. 143, Nr. 7, 1997, Seiten 2135-2143, XP008054300 ISSN: 1350-0872 * |
| OTA Y ET AL: "Butirosin-biosynthetic gene cluster from Bacillus circulans." THE JOURNAL OF ANTIBIOTICS. OCT 2000, Bd. 53, Nr. 10, Oktober 2000 (2000-10), Seiten 1158-1167, XP002349775 ISSN: 0021-8820 -& DATABASE NCBI SEQUENCE DATABASE Washington, US; 25. November 2000 (2000-11-25), Y. OTA ET AL.: "Bacillus circulans butirosin gene cluster" XP002349783 gefunden im GENEBANK Database accession no. AB033991 * |
| PISSOWOTZKI K ET AL: "GENETICS OF STREPTOMYCIN PRODUCTION IN STREPTOMYCES-GRISEUS MOLECULAR STRUCTURE AND PUTATIVE FUNCTION OF GENES STRELMB2N" MOLECULAR AND GENERAL GENETICS, Bd. 231, Nr. 1, 1991, Seiten 113-123, XP002349934 ISSN: 0026-8925 * |
| S. BUDAVARI: "The Merck Index, Twelfth Edition" 1996, MERCK &CO. INC. , WHITEHOUSE STATION, NJ, US , XP002349779 *Butirosin* Spalte 1559 * |
| TAMEGAI HIDEYUKI ET AL: "Identification of L-glutamine: 2-Deoxy-scyllo-inosose aminotransferase required for the biosynthesis of butirosin in Bacillus circulans" JOURNAL OF ANTIBIOTICS (TOKYO), Bd. 55, Nr. 8, August 2002 (2002-08), Seiten 707-714, XP008054312 ISSN: 0021-8820 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009058679A1 (fr) * | 2007-10-30 | 2009-05-07 | Danisco Us Inc., Genencor Division | Protéase de streptomyces |
| US7618801B2 (en) | 2007-10-30 | 2009-11-17 | Danison US Inc. | Streptomyces protease |
| US7879788B2 (en) | 2007-10-30 | 2011-02-01 | Danisco Us Inc. | Methods of cleaning using a streptomyces 1AG3 serine protease |
| CN101842480B (zh) * | 2007-10-30 | 2013-07-10 | 丹尼斯科美国公司 | 链霉菌蛋白酶 |
| EP2298879A1 (fr) * | 2008-06-05 | 2011-03-23 | Meiji Seika Kaisha, Ltd. | Procédé d'amplification de l'adn dans une cellule |
| EP2298879A4 (fr) * | 2008-06-05 | 2013-02-20 | Meiji Seika Kaisha | Procédé d'amplification de l'adn dans une cellule |
| US8440400B2 (en) | 2008-06-05 | 2013-05-14 | Meiji Seika Pharma Co., Ltd. | Process for amplifying DNA in cells |
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| Publication number | Publication date |
|---|---|
| WO2005095591A3 (fr) | 2006-07-20 |
| DE102004017141A1 (de) | 2005-12-01 |
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