WO2005095591A2 - Novel genes from a biosynthesis gene cluster for aminoglycoside antibiotic synthesis and the thus obtained novel aminoglycoside antibiotics - Google Patents
Novel genes from a biosynthesis gene cluster for aminoglycoside antibiotic synthesis and the thus obtained novel aminoglycoside antibiotics 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
The invention relates to novel genes obtainable from aminoglycoside-producing microorganisms, to novel gene clusters formed from the novel and/or known genes of said microorganisms, to the expression products of the genes, the transport vehicles thereof or of the gene clusters and to transformed cells containing said genes or gene clusters. Said invention also relates to methods for biologically producing aminoglycosides, methods for combinatory synthesis of aminoglycoside derivatives, to novel aminoglycosides, to the use thereof and to pharmaceutical compositions containing said aminoglycosides.
Description
Neue Gene aus Biosynthese Genclustern zur Synthese von Aminoglycosid-Antibiotika sowie damit herstellbare neue Aminoglycosid-Antibiotika New genes from biosynthesis Gene clusters for the synthesis of aminoglycoside antibiotics and new aminoglycoside antibiotics that can be produced with them
Gebiet der Erfindung.Field of the Invention.
Die Erfindung betrifft neue Gene aus Aminoglycosid- produzierenden Mikroorganismen, neue Gencluster, welche aus neuen und/oder bekannten Genen dieser Mikroorganismen gebildet sind, Expressionsprodukte dieser Gene, Transformationsvehikel enthaltend solche Gene oder Gencluster, transformierte Zellen enthaltend solche Gene oder Genklus- ter, Verfahren zur biotechnologischen Herstellung von Ami- noglycosiden, Verfahren zur kombinatorischen Biosynthese von Arciinoglycosidderivaten, neue Aminoglycoside, Verwendungen solcher Aminoglycoside und pharmazeutische Zusammensetzungen enthaltend solche Aminoglycoside.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.
Hintergrund der Erfindung und Stand der TechnikBackground of the Invention and Prior Art
Aminoglycosid-Antibiotika sind Substanzen, die durch Eingriff in die Proteinsynthese (Bindung an 30s Unterein- heiten der bakteriellen Ribosomen und Inhibierung der Translation oder Blockierung der Bildung von korrekten Peptidbindung zwischen Aminosäuren) auf grampositive und gramnegative Bakterien abtötend wirken. Beispielhaft für Zielbakterien seien insbesondere E. coli und Klebsieila genannt. Mittels Aminoglycosid-Antibiotika können auch multiresistente Erregerstämme erfasst werden, weshalb Aminoglycosid-Antibiotika insbesondere auch als Reserveantibiotika für Patienten mit lebensgefährlichen Infektionen
Verwendung- finden. Dies ist auch damit indiziert, dass Kreuzresistenzen zu anderen Antibiotikagruppen selten sind.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.
Bei biosynthetisierten Aminoglycosiden handelt es sich prinzipiell um Sekundär etabolite der für die Synthese eingesetzten Mikroorganismen. Die für die Synthese relevanten Enzyme bzw. Enzymgruppen werden von den Genen bzw. Genclustern der Mikroorganismen exprimiert. Die Kombina- tion solcher Gene bzw. Gencluster bestimmt letztendlich die spezifische Struktur des erzeugten Aminoglycosids . Durch unterscheidliche Kombination der Gene bzw. Gencluster in gentechnologisch modifizierten Mikroorganismen können diese neue Derivate der natürlicherweise hergestellten Aminoglycoside hergestellt werden. Durch Kombinatorik der Gene und/oder Gencluster können eine Vielzahl von unterschiedlichen Derivaten erzeugt werden, welche wiederum in Screeningverfahren auf Wirksamkeit, insbesondere erhöhte Wirksamkeit gegenüber bekannten Aminoglycosiden, und/oder reduzierte Nebenwirkungen, getestet werden können.In principle, 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. By differently combining the genes or gene clusters in genetically modified microorganisms, these new derivatives of the naturally produced aminoglycosides can be produced. By combining 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.
Hinsichtlich bekannter Aminoglycosid-Antibiotika werden zunehmend Resistenzen bekannt. Zur Bekämpfung von solchen resistenten Erregern ist es wünschenswert, neue Aminogly- cosid Derivate zu finden, welche gegen die resistenten Erreger wirksam sind.Resistance to known aminoglycoside antibiotics is growing. To combat such resistant pathogens, it is desirable to find new aminoglycoside derivatives which are effective against the resistant pathogens.
Technisches Problem der ErfindungTechnical problem of the invention
Der Erfindung liegt daher das technische Problem zu Grunde, Mittel zur Schaffung von neuen Aminoglycosiden,
insbesondere mit verbesserter Wirkung und/oder verringerten Nebenwirkungen, zur Verfügung zu stellen.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.
Grundzüge der Erfindung und Ausführungsformen.Basics of the invention and embodiments.
Zur Lösung dieses technischen Problems lehrt die Erfindung ein isoliertes Protein oder Peptid enthaltend, insbesondere bestehend aus, einer der offenbarten Aminosäurense- guenzen. Erfindungsgemäße Proteine oder Peptide können in einer Zelle zur Biosynthese exprimiert werden, es ist jedoch auch ein Import extern erzeugten Proteins oder Pep- tids in eine die Biosynthese ausführende Zelle möglich.To solve this technical problem, 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.
Das Protein oder Peptid ist vorzugsweise für einen Teilsyntheseschritt der Biosynthese eines Aminoglycosids, insbesondere eines Aminoglycosid-Antibiotikums, beispielsweise ausgewählt aus der Gruppe bestehend aus "Butirosine, Gentamicine, Neomycine, Fortimicine, Tobramy- eine, Apramycine, Paromomycine, Hygromycine B, Ribostamy- cine, Sagamicine, Sisomicine, Kana ycine, Nebramycine, Seldo ycine, Destomycine, Istamycine, Sannamycine, Dac- ti icine, Sporaricine, Bluensomycine, Ashimycine, Livido- myeine und Spectino ycine" fun tional.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.
Die Erfindung betrifft weiterhin eine isolierte Nuklein- säure, insbesondere DNA, beispielsweise genomische DNA, oder RNA, insbesondere mRNA, codierend für ein erfindungs- gemäßes Protein oder Peptid.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.
Die Erfindung umfasst weiterhin ein isoliertes Transformationsvehikel , insbesondere Plasmid oder Cosmid, enthaltend eine erfindungsgemäße Nukleinsäure . Es kann eine Mehrzahl ,
insbesondere 1 bis 50, verscheidener erfindungsgemäßer Nukleinsäuren enthalten. Dabei wird es sich insbesondere empfehlen, wenn durch die Mehrzahl der Nukleinsäuren ein Biosynthesecluster oder ein Teil eines Biosyntheseclusters für ein Aminoglycosid, insbesondere ein Aminoglycosid- Antibiotikum, gebildet ist. Das Transformationsvehikel kann zusätzlich zumindest eine regulatorische Nuklein- säuresequenz enthalten, wobei die Nukleinsäure unter der Kontrolle der regulatorischen Nukleinsäureseguenz, insbe- sondere eines Promotors, steht. Selbstverständlich können ein oder mehrere regulatorische Sequenzen mit der Maßgabe eingerichtet sein, dass eine Mehrzahl von Nukleinsäuren, insbesondere ein Gencluster oder ein Teil eines Genclus- ters kontrolliert werden.The invention further comprises an isolated transformation vehicle, in particular a plasmid or cosmid, containing a nucleic acid according to the invention. There can be a plurality in particular contain 1 to 50 different nucleic acids according to the invention. It will be particularly recommended if the majority of the nucleic acids form a biosynthesis cluster or part of a biosynthesis cluster for an aminoglycoside, in particular an aminoglycoside antibiotic. 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. Of course, 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.
Die Erfindung betrifft weiterhin eine Zelle enthaltend eine e findungsgemäße Nukleinsäure oder mehrere verschiedene solcher Nukleinsäuren und/oder ein erfindungsgemäßes Protein oder Peptid oder mehrere verschiedene solcher- Proteine oder Peptide, wobei die Zelle optional mit einer erfindungsgemäßen Nukleinsäure oder mehreren verschiedenen solcher Nukleinsäuren transformiert sein kann. Hierbei kann eine gewünschte Derivatisierung eines natürlicherweise von der Zelle synthetisierten Aminoglyco- sids dadurch erreicht werden, dass in einem Aminoglycosid- synthese Gencluster der Zelle an Stelle oder zusätzlich zu einem natürlichen Gen für einen definierten Teilsyntheseschritt ein hiervon verschiedenes fremdes Gen für einen von dem definierten Teilsyntheseschritt verschiedenen an- dere definierten Teilsyntheseschritt eingeführt ist. Dies kann durch Konstruktion und Einführung des gesamten Amino- glycosidsynthese Genclusters oder Teilen hiervon erfolgen. Es wird gleichsam eine mutierte Biosynthese
maßgeschneidert nach Maßgabe der gewünschten Derivatis- ierung. Es ist möglich, ein natürlicherweise enthaltenes Gen codierend für ein Protein oder Peptid, welches für einen Teilsyntheseschritt der Biosynthese eines Aminogly- cosids, insbesondere eines Aminoglycosid-Antibiotikums, funktional ist, zu inhibieren, insbesondere zu deletieren. Dies kann auch für mehrere natürlicherweise enthaltene solche Gene erfolgen.The invention further relates to a cell containing a nucleic acid according to the invention or several different such nucleic acids and / or a protein or peptide according to the invention or several different such proteins or peptides, wherein the cell can optionally be transformed with a nucleic acid according to the invention or several different such nucleic acids. In this case, a desired derivatization of an aminoglycoside naturally synthesized by the cell can be achieved in that in an aminoglycoside synthesis, gene clusters of the cell instead of or in addition to a natural gene for a defined partial synthesis step, a different gene for a different part from the defined partial synthesis step various other defined partial synthesis step is introduced. This can be done by designing and introducing all or part of the aminoglycoside synthesis gene cluster. It becomes a mutated biosynthesis tailor-made according to the desired derivatization. It is possible to inhibit, in particular to delete, a naturally contained gene coding for a protein or peptide which is functional for a partial synthesis step in the biosynthesis of an aminoglycoside, in particular an aminoglycoside antibiotic. This can also be done for several naturally contained genes.
Geeignete Zellen sind vorzugsweise ausgewählt aus der Gruppe bestehend aus "Bacillus circulans, insbesondere NRRL B3312, Micromonospora echinosporea, insbesondere DSM 43036, Streptom. kana yceticus, insbesondere DSM 40500, Streptom. fradiae, insbesondere DSM 2458, Micromonospora olicasterspora, insbesondere DSM 43868, Streptom. tene- brarius, insbesondere DSM 40477, Streptom. rimosus ssp. paromomycinus , insbesondere ATCC 2455, Streprom. hygro- scopicus ssp. hygroscopicus, insbesondere DSM 40578, Streprom. ribosidificus, insbesondere ATCC 21294, Micromonospora spec . , insbesondere DSM 43912, Micromonospora inyoensis, insbesondere NRRL 3292, Streptoal- loteichus hindustanus, insbesondere DSM 44523, Streptom. hofunensis sp . nov, Streptom. rimofaciens, insbesondere ATCC 21066, Streptom. ten imariensis, insbesondere ATCC 31603, Streptom. sannaensis, insbesondere IFO 14239, Dac- tylosporangium matsuzakiense, insbesondere DSM 43810, Sac- charopolyspora hirsuta, insbesondere ATCC 20501, Streptom. griseus N2-3-11, insbesondere ATCC 23345, Streptom. glaucescens GLA.O, insbesondere ETH 22794, Streptom. blu- ensis, insbesondere DSM 40564, Streptom. griseus FT3-4, Streptom. flavopersicus, insbesondere NRLL 2820 A In der Tabelle I sind die von diesen Stämmen herstellbaren Antibiotika zusammengefasst . Es versteht sich, dass eine
erfindungsgemäße Zelle eine mit einem erfindungsgemäßen Transformationsvehikel erzeugte Mutante der vorstehenden Stämme ist und dass das damit erzeugbare Antibiotikum derivatisiert ist. Die Erfindung u fasst auch Aminoglycoside, insbesondere Aminoglycosid-Antibiotika, welche dadurch erhältlich sind, dass eine erfindungsgemäße Zelle kultiviert wird, und dass nach Kultivierung das Aminoglycosid aus der Zelle und/oder aus dem Kultivierungsüberstand isoliert wird. Ein er- findungsgemäßes Aminoglycosid ist zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung von bakteriellen oder viralen Infektionen, insbesondere von Infektionen mit gramnegativen Bakterien, beispielsweise mit E. coli oder Klebsiella, geeignet. Dabei kann die Biosyn- these dahingehend mutiert sein, dass das neueSuitable 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. It is understood that 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
Aminoglycosid-Antibiotikum eine verbesserte Wirksamkeit gegenüber bekannten Wirkstoffen aufweist. Es ist aber auch möglich, dass ein erfindungsgemäßes Aminαglycosid-Anti- biotikum "lediglich" als Ersatztherapie bei Resistenz gegen einen bekannten Wirkstoff Verwendung findet. Dann liegt der Vorteil darin, dass mittels des erfindungsgemäßen Wirkstoffes überhaupt erst wieder eine Therapie möglich ist. Besonders ünschenwert sind jedoch auch neue Aminoglycosid-Antibiotika mit reduzierten Nebenwirkungen.Aminoglycoside antibiotic has an improved effectiveness over known active ingredients. However, it is also possible for an amine αglycoside 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.
Die Erfindung betrifft des Weiteren eine pharmazeutische Zusammensetzung enthaltend ein erfindungsgemäßes Aminoglycosid oder mehrere solcher Aminoglycoside in physiologisch wirksamer Dosis. Zusätzlich enthalten können sein ga- lenische Hilfs- und/oder Trägerstoffe. Die galenische Herrichtung einer erfindungsgemäßen pharmazeutischen Zusammensetzung kann in fachüblicher Weise erfolgen. Als Gegenionen für ionische Verbindungen kommen beispielsweise
Na+, K+, Li+ oder Cyclohexylammonium in Frage. Geeignete feste oder flüssige galenische Zubereitungsformen sind beispielsweise Granulate, Pulver, Dragees, Tabletten, (Mikro-) Kapseln, Suppositorien, Sirupe, Säfte, Suspen- sionen, Emulsionen, Tropfen oder Lösungen zur Injektion (i.V., i.p., i.m., s.c.) oder Vernebelung (Aerosole), transdermale Systeme, sowie Präparate mit protrahierter Wirkstoff-Freigabe, bei deren Herstellung übliche Hilfsmittel wie Trägerstoffe, Spreng-, Binde-, Überzugs-, Quellungs-, Gleit- oder Schmiermittel, Geschmacksstoffe, Süßungsmittel und Lösungsvermittler, Verwendung finden. Als Hilfsstoffe sei Magnesiumcarbonat, Titandioxid, Lac- tose, Mannit und andere Zucker, Talcum, Milcheiweiß, Gelatine, Stärke, Zellulose und ihre Derivate, tierische und pflanzliche Öle wie Lebertran, Sonnenblumen-, Erdnuss- oder Sesa öl, Polyethylenglycole und Lösungsmittel, wie etwa steriles Wasser und ein- oder mehrwertige Alkohole, beispielsweise Glycerin, genannt. Eine erfindungsgemäße pharmazeutische Zusammensetzung ist dadurch herstellbar, dass mindestens ein erfindungsgemäß verwendeter Wirkstoff in definierter Dosis mit einem pharmazeutisch geeigneten und physiologisch verträglichen Träger und ggf. weiteren geeigneten Wirk-, Zusatz- oder Hilfsstoffen mit definierter 'Inhibitordosis gemischt und zu der gewünschten Darreichungsform hergerichtet ist. Vorzugsweise ist eine erfindungsgemäße pharmazeutische Zusammensetzung galenisch hergerichtet zur oralen oder parenteralen Gabe.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. Magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talcum, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesa oil, polyethylene glycols and solvents such as such as sterile water and mono- or polyhydric alcohols, such as glycerin. 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.
Im folgenden wird die Erfindung durch ausführliche Beschreibung von besonderen Ausführungsformen erläutert.In the following the invention is explained by a detailed description of special embodiments.
In diesen Ausführungsformen können einzelne Merkmale der Erfindung allein oder in Kombination mit anderen Merkmalen verwirklicht sein. Die beschriebenen besonderen
Ausführungsformen dienen lediglich zur Erläuterung und zum besseren Verständnis der Erfindung und sind in keiner Weise einschränkend zu verstehen.In these embodiments, individual features of the invention can be implemented alone or in combination with other features. The special described Embodiments are used only for explanation and for a better understanding of the invention and are not to be understood in any way restrictive.
Beispiel 1: Butirosin Cluster Liste 1 beschreibt Aminosäuresequenzen des Butirosin Biosynthese Genclusters, einschließlich der Funktionen der einzelnen Gene.Example 1: Butirosin Cluster List 1 describes amino acid sequences of the butirosin biosynthesis gene cluster, including the functions of the individual genes.
Beispiel 2: Gentamicin Cluster Liste 2 beschreibt Aminosäuresequenzen des Gentamicin Biosynthese Genclusters, einschließlich der Funktionen der einzelnen Gene.Example 2: Gentamicin Cluster List 2 describes amino acid sequences of the gentamicin biosynthesis gene cluster, including the functions of the individual genes.
Beispiel 3 : Kanamycin Cluster Liste 3 beschreibt Aminosäuresequenzen des Kanamycin Biosynthese Genclusters, einschließlich der Funktionen der einzelnen Gene.Example 3: Kanamycin Cluster List 3 describes amino acid sequences of the kanamycin biosynthesis gene cluster, including the functions of the individual genes.
Beispiel 4: Neomycin Cluster Liste 4 beschreibt Aminosäuresequenzen des Neumycin Biosynthese Genclusters, einschließlich der Funktionen der einzelnen Gene.Example 4: Neomycin Cluster List 4 describes amino acid sequences of the Neumycin biosynthesis gene cluster, including the functions of the individual genes.
Beispiel 5: Fortimicin Cluster Liste 5 beschreibt Aminosäuresequenzen des Fortimicin Biosynthese Genclusters, einschließlich der Funktionen der einzelnen Gene.Example 5: Fortimicin Cluster List 5 describes amino acid sequences of the fortimicin biosynthesis gene cluster, including the functions of the individual genes.
Beispiel 6: Tobramycin/Apramycin Cluster Die Listen 6 und 12 beschreiben Aminosäuresequenzen des Tobramycin/Apramycin Biosynthese Genclusters, einschließlich der Funktionen der einzelnen Gene.
Beispiel 7 : Paromomycin Cluster Listen 7 und 11 beschreiben Aminosäuresequenzen des Paromomycin Biosynthese Genclusters, einschließlich der Funktionen der einzelnen Gene.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.
Beispiel 8: Hygromycin B Cluster Liste 8 beschreibt Aminosäuresequenzen des Hygromycin B Biosynthese Genclusters, einschließlich der Funk- tionen der einzelnen Gene.Example 8: Hygromycin B Cluster List 8 describes amino acid sequences of the hygromycin B biosynthesis gene cluster, including the functions of the individual genes.
Beispiel 9: Ribostamycin Cluster Liste 9 beschreibt Aminosäuresequenzen des Ribostamycin Biosynthese Genclusters, einschließlich der Funktionen der einzelnen Gene.Example 9: Ribostamycin Cluster List 9 describes amino acid sequences of the ribostamycin biosynthesis gene cluster, including the functions of the individual genes.
Beispiel 10: Lividomycin Cluster Liste 10 beschreibt Aminosäuresequenzen des Lividomycin Biosynthese Genclusters, einschließlich der Funk- tionen der einzelnen Gene.Example 10: Lividomycin Cluster List 10 describes amino acid sequences of the lividomycin biosynthesis gene cluster, including the functions of the individual genes.
Beispiel 11: Istamycin Cluster Liste 13 beschreibt Aminosäuresequenzen des Istamycin Biosynthese Genclusters, einschließlich der Funktionen der einzelnen Gene.Example 11: Istamycin Cluster List 13 describes amino acid sequences of the istamycin biosynthesis gene cluster, including the functions of the individual genes.
Beispiel 12 : Apramycin Cluster Liste 14 beschreibt Aminosäuresequenzen des Apramycin Biosynthese Genclusters, einschließlich der Funktionen der einzelnen Gene.
Tabelle IExample 12: Apramycin Cluster List 14 describes amino acid sequences of the apramycin biosynthesis gene cluster, including the functions of the individual genes. Table I
Produzentenstamm Stammnrmmer Produziertes A inoglykosid- AntibiotüaimProducer strain strain number Produced A inoglycoside antibiotic
Bacillus (B.) circulans KRRL B3312 Butirosin Streptomyces (S.) ribosidificus ATCC 21294 Ribostamycin S.fradiae DSM 40063 Neomycin S. rimosus ssp. paromomycinus ATCC 2455 ParomomycinBacillus (B.) circulans KRRL B3312 Butirosin Streptomyces (S.) ribosidificus ATCC 21294 Ribostamycin S.fradiae DSM 40063 Neomycin S. rimosus ssp. paromomycinus ATCC 2455 paromomycin
Micromonospora (M.) DSM 43036 Gentamicin echinospora M. spec. DSM 43912 Sagamicin M. inyoensis NRRL 3292 SisomicinMicromonospora (M.) DSM 43036 Gentamicin echinospora M. spec. DSM 43912 Sagamicin M. inyoensis NRRL 3292 Sisomicin
S. kanamyceticus DSM 40500 Kanamycrn S, tenebraήus DSM 40477 Apramycin/Nebramycin Streptoälloteichus hindustanus DSM 44523 Apramycin/Tobramycin S. hofunensis sp. nov. Seldorn cinS. kanamyceticus DSM 40500 Kanamycrn S, tenebraήus DSM 40477 Apramycin / Nebramycin Streptoalloteichus hindustanus DSM 44523 Apramycin / Tobramycin S. hofunensis sp. nov. Seldorn cin
S. hygroscopicus ssp. DSM 4057S Hygromycin B hygroscopicus S. rimofaciens ATCC 21066 DestomycinS. hygroscopicus ssp. DSM 4057S Hygromycin B hygroscopicus S. rimofaciens ATCC 21066 Destomycin
M. olivasterospora DSM 43868 Fortimicin A S. tenjimariensis ATCC 31603 Istamycin S. sannaensis IFO 14239 S-iiiαamycin Dactylosporangium matsuzakiense DSM 43810 Dactimicin Saccharopolyspora hirsuta ATCC 20501 SporaricinM. olivasterospora DSM 43868 Fortimicin A S. tenjimariensis ATCC 31603 Istamycin S. sannaensis IFO 14239 S-iiiαamycin Dactylosporangium matsuzakiense DSM 43810 Dactimicin Saccharopolyspora hirsuta ATCC 20501 Sporaricin
S. griseus N2-3-11 ATCC 23345 Streptomycin S. glaucescens GLA.O ETH 22794 Streptomycin S. bluensis DSM 40564 Bluensomyciα S. griseus FT3-4 Asrώiiycin S. flavopersicus NRRL 2820 Spectinornycin.
S. griseus N2-3-11 ATCC 23345 Streptomycin S. glaucescens GLA.O ETH 22794 Streptomycin S. bluensis DSM 40564 Bluensomyciα S. griseus FT3-4 Asrώiiycin S. flavopersicus NRRL 2820 Spectinornycin.
Claims
1. Isoliertes Protein oder Peptid enthaltend, insbeson- dere bestehend aus, einer der offenbarten Aminosäurensequenzen .1. Isolated protein or peptide containing, in particular consisting of, one of the disclosed amino acid sequences.
2. Protein oder Peptid nach Anspruch 1, wobei das Pro- tein oder Peptid für einen Teilsyntheseschritt der Biosynthese eines Aminoglycosids, insbesondere eines A inoglycosid-Antibiotikums, beispielsweise ausgewählt aus der Gruppe bestehend aus "Butirosine, Gentamicine, Neomycine, Fortimicine, Tobramycine, Apramycine, Paromomycine, Hygromycine B, Ribostamy- cine, Sagamicine, Sisomicine, Kanamycine, Nebramy- cine, Seldomycine, Destomycine, Istamycine, Sannamycine, Dactimicine, Sporaricine, Bluensomycine, Ashi ycine, Lividomycine und Spectinomycine" funk- tional ist.2. Protein or peptide according to claim 1, wherein the protein or peptide 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, apramycins , Paromomycine, Hygromycine B, Ribostamycin, Sagamicine, Sisomicine, Kanamycine, Nebramycin, Seldomycine, Destomycine, Istamycine, Sannamycine, Dactimicine, Sporaricine, Bluensomycine, Ashi ycine, Lividomycine ist and.
3. Isolierte Nukleinsäure, insbesondere DNA, beispielsweise genomische DNA, oder RNA, insbesondere mRNA, codierend für ein Protein oder Peptid gemäß Anspruch 1 oder 2.3. Isolated nucleic acid, in particular DNA, for example genomic DNA, or RNA, in particular mRNA, coding for a protein or peptide according to claim 1 or 2.
4. Isoliertes Transformationsvehikel, insbesondere Pias- mid oder Cosmid, enthaltend eine Nukleinsäure nach Anspruch 3. 4. Isolated transformation vehicle, in particular plasmid or cosmid, containing a nucleic acid according to claim 3.
5. Isoliertes Transformationsvehikel nach Anspruch 4, enthaltend eine Mehrzahl, insbesondere 1 bis 50, ver- scheidener Nukleinsäuren.5. An isolated transformation vehicle according to claim 4, containing a plurality, in particular 1 to 50, of different nucleic acids.
6. Isoliertes Transformationsvehikel nach Anspruch 4 oder 5, zusätzlich enthaltend zumindest eine regulatorische Nukleinsäuresequenz, wobei die Nukleinsäure unter der Kontrolle der regulatorischen Nukleinsäure- sequenz, insbesondere eines Promotors, steht.6. An isolated transformation vehicle according to claim 4 or 5, additionally containing at least one regulatory nucleic acid sequence, the nucleic acid being under the control of the regulatory nucleic acid sequence, in particular a promoter.
7. Zelle enthaltend eine Nukleinsäure oder mehrere verschiedene Nukleinsäuren nach Anspruch 3 und/oder ein Protein oder Peptid oder mehrere verschiedene Proteine oder Peptide nach Anspruch 1 oder 2 , welche optional mit einer Nukleinsäure oder mehreren verschiedenen Nukleinsäuren nach Anspruch 3 transformiert ist.7. Cell containing a nucleic acid or several different nucleic acids according to claim 3 and / or a protein or peptide or several different proteins or peptides according to claim 1 or 2, which is optionally transformed with one nucleic acid or several different nucleic acids according to claim 3.
Zelle nach Anspruch 7, welche erhältlich ist durch Transformation mit einem Transformationsvehikel nach einem der Ansprüche 4 bis 6.The cell of claim 7, which is obtainable by transformation with a transformation vehicle according to one of claims 4 to 6.
9. Zelle nach Anspruch 7 oder 8, wobei ein natürlicherweise enthaltenes Gen codierend für ein Protein oder Peptid, welches für einen Teilsyntheseschritt der Biosynthese eines Aminoglycosids, insbesondere eines A inoglycosid-Antibiotikums, funktional ist, inhibiert, insbesondere deletiert, ist, oder wobei mehrere natürlicherweise enthaltene solche Gene inhibiert, insbesondere deletiert, sind.9. Cell according to claim 7 or 8, wherein a naturally contained gene coding for a protein or peptide which is functional for a partial synthesis step of the biosynthesis of an aminoglycoside, in particular an aminoglycoside antibiotic, is inhibited, in particular deleted, or wherein several naturally contained such genes are inhibited, in particular deleted.
10. Zelle nach einem der Ansprüche 7 bis 9, ausgewählt aus der Gruppe bestehend aus "Bacillus circulans, insbesondere NRRL B3312, Micromonospora echinosporea, insbesondere DSM 43036, Streptom. kanamyceticus, insbesondere DSM 40500, Streptom. fradiae, insbesondere DSM 2458, Micromonospora olicasterspora, insbesondere DSM 43868, Streptom. tenebrarius, insbesondere DSM 40477, Streptom. rimosus ssp. paromomycinus, insbesondere ATCC 2455, Streprom. hygroscopicus ssp. hygroscopicus, insbesondere DSM 40578, Streprom. ribosidificus, insbesondere ATCC 21294, Micromonospora spec, insbesondere DSM 43912, Micromonospora inyoensis, insbesondere NRRL 3292, Streptoalloteichus hindustanus, insbesondere DSM 44523, Streptom. hofunensis sp. nov, Streptom. rimofaciens, insbeson- dere ATCC 21066, Streptom. tenj imariensis, insbesondere ATCC 31603, Streptom. sannaensis, insbesondere IFO 14239, Dactylosporangium matsuzakiense, insbesondere DSM 43810, Saccharopolyspora hirsuta, insbesondere ATCC 20501, Streptom. griseus N2-3-11, insbesondere ATCC 23345, Streptom. glaucescens GLA.O, insbesondere ETH 22794, Streptom. bluensis, insbesondere DSM 40564, Streptom. griseus FT3-4, Streptom. flavopersicus, insbesondere NRLL 2820".10. Cell according to one of claims 7 to 9, selected from the group consisting of "Bacillus circulans, in particular NRRL B3312, Micromonospora echinosporea, in particular DSM 43036, Streptom. Kanamyceticus, in particular DSM 40500, Streptom. Fradiae, in particular DSM 2458, Micromonospora olicasterspora , in particular DSM 43868, Streptom. tenebrarius, in particular DSM 40477, Streptom. rimosus ssp. paromomycinus, in particular ATCC 2455, Streprom. hygroscopicus ssp. hygroscopicus, in particular DSM 40578, Strepromom. ribosidificus, in particular ATCC 21294, Micromonospora spec., in particular DSM 43 Micromonospora inyoensis, in particular NRRL 3292, Streptoalloteichus hindustanus, in particular DSM 44523, Streptom. Hofunensis sp. Nov, Streptom. Rimofaciens, in particular ATCC 21066, Streptom. Tenj imariensis, in particular ATCC 31603, Streptom , in particular DSM 43810, Saccharopolyspora hirsuta, in particular ATCC 20501, Stre ptom. griseus N2-3-11, especially ATCC 23345, streptom. glaucescens GLA.O, especially ETH 22794, streptom. bluensis, especially DSM 40564, streptom. griseus FT3-4, streptom. flavopersicus, especially NRLL 2820 ".
11. Verfahren zur Herstellung einer Zelle nach einem der Ansprüche 7 bis 10, wobei die Zelle mit einem Tranformationsvehikel nach einem der Ansprüche 4 bis 6 transformiert wird.11. A method for producing a cell according to any one of claims 7 to 10, wherein the cell with a Transformation vehicle according to one of claims 4 to 6 is transformed.
12. Aminoglycosid, insbesondere Aminoglycosid- Antibiotikum, dadurch erhältlich, dass eine Zelle nach einem der Ansprüche 7 bis 10 kultiviert wird, und dass nach Kultivierung das Aminoglycosid aus der Zelle und/oder aus dem Kultivierungsüberstand isoliert wird.12. aminoglycoside, in particular aminoglycoside antibiotic, obtainable in that a cell is cultivated according to one of claims 7 to 10, and that after culturing the aminoglycoside is isolated from the cell and / or from the cultivation supernatant.
13. Verfahren zur Herstellung eines Aminoglycosids, insbesondere eine Aminoglycosid-Antibiotikums, wobei eine Zelle nach einem der Ansprüche 7 bis 10 kultiviert wird, und wobei nach Kultivierung das Aminoglycosid aus der Zelle und/oder aus dem Kultivierungsüberstand isoliert wird.13. A method for producing an aminoglycoside, in particular an aminoglycoside antibiotic, wherein a cell is cultivated according to one of claims 7 to 10, and wherein after culturing the aminoglycoside is isolated from the cell and / or from the cultivation supernatant.
14. Verwendung eines Aminoglycosids nach Anspruch 12 zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung von bakteriellen oder viralen Infektionen, insbesondere von Infektionen mit gramposi- tiven oder gramnegativen Bakterien, beispielsweise mit E. coli oder Klebsiella.14. Use of an aminoglycoside according to claim 12 for the manufacture of a pharmaceutical composition for the treatment of bacterial or viral infections, in particular infections with gram-positive or gram-negative bacteria, for example with E. coli or Klebsiella.
15. Pharmazeutische Zusammensetzung enthaltend ein Amino- glycosid oder mehrere Aminoglycoside nach Anspruch 12 in physiologisch wirksamer Dosis. 15. Pharmaceutical composition containing an aminoglycoside or more aminoglycosides according to claim 12 in a physiologically effective dose.
16. Pharmazeutische Zusammensetzung nach Anspruch 15, zusätzlich enthalten galenische Hilfs- und/oder Trägerstoffe.16. Pharmaceutical composition according to claim 15, additionally contain pharmaceutical auxiliaries and / or carriers.
17. Pharmazeutische Zusammensetzung nach Anspruch 15 oder 16, galenisch hergerichtet zur oralen oder parenter- alen Gabe.17. Pharmaceutical composition according to claim 15 or 16, galenically prepared for oral or parenteral administration.
18. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 15 bis 17, wobei ein Aminoglycosid oder mehrere Aminoglycoside nach Anspruch 12 in physiologisch wirksamer Dosis mit galenischen Hilfs- und/oder Trägerstoffen gemischt und galenisch hergerichtet, insbesondere zur oralen oder parenteralen Gabe, werden. 18. A method for producing a pharmaceutical composition according to any one of claims 15 to 17, wherein an aminoglycoside or more aminoglycosides according to claim 12 are mixed in a physiologically effective dose with galenic auxiliaries and / or carriers and galenically prepared, in particular for oral or parenteral administration ,
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009058679A1 (en) * | 2007-10-30 | 2009-05-07 | Danisco Us Inc., Genencor Division | Streptomyces protease |
| EP2298879A1 (en) * | 2008-06-05 | 2011-03-23 | Meiji Seika Kaisha, Ltd. | Method for amplification of dna in cell |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0035770A2 (en) * | 1980-03-07 | 1981-09-16 | INTERx RESEARCH CORPORATION | An orally administered drug form comprising a glycosidic antibiotic and an adjuvant |
| EP0204549A2 (en) * | 1985-06-07 | 1986-12-10 | Eli Lilly And Company | Method of isolating antibiotic biosynthetic genes |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20030082708A (en) * | 2002-04-18 | 2003-10-23 | 주식회사 바이오홀딩스 | Gene and amino acid sequences of bluensomycin biosynthesis enzyme and transformant thereof |
-
2004
- 2004-04-01 DE DE200410017141 patent/DE102004017141A1/en not_active Ceased
-
2005
- 2005-03-15 WO PCT/DE2005/000499 patent/WO2005095591A2/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0035770A2 (en) * | 1980-03-07 | 1981-09-16 | INTERx RESEARCH CORPORATION | An orally administered drug form comprising a glycosidic antibiotic and an adjuvant |
| EP0204549A2 (en) * | 1985-06-07 | 1986-12-10 | Eli Lilly And Company | Method of isolating antibiotic biosynthetic genes |
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 (en) * | 2007-10-30 | 2009-05-07 | Danisco Us Inc., Genencor Division | Streptomyces protease |
| 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 (en) * | 2007-10-30 | 2013-07-10 | 丹尼斯科美国公司 | Streptomyces protease |
| EP2298879A1 (en) * | 2008-06-05 | 2011-03-23 | Meiji Seika Kaisha, Ltd. | Method for amplification of dna in cell |
| EP2298879A4 (en) * | 2008-06-05 | 2013-02-20 | Meiji Seika Kaisha | METHOD FOR AMPLIFYING DNA IN A CELL |
| US8440400B2 (en) | 2008-06-05 | 2013-05-14 | Meiji Seika Pharma Co., Ltd. | Process for amplifying DNA in cells |
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