EP1740595A1 - Macrolactones polycyliques - Google Patents

Macrolactones polycyliques

Info

Publication number
EP1740595A1
EP1740595A1 EP04765521A EP04765521A EP1740595A1 EP 1740595 A1 EP1740595 A1 EP 1740595A1 EP 04765521 A EP04765521 A EP 04765521A EP 04765521 A EP04765521 A EP 04765521A EP 1740595 A1 EP1740595 A1 EP 1740595A1
Authority
EP
European Patent Office
Prior art keywords
substance
bacteria
substances
protozoa
microorganism
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04765521A
Other languages
German (de)
English (en)
Inventor
Hans-Peter Fiedler
Roderich SÜßMUTH
Hans ZÄHNER
Alan Bull
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eberhard Karls Universitaet Tuebingen
Original Assignee
Eberhard Karls Universitaet Tuebingen
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE10353300A external-priority patent/DE10353300A1/de
Application filed by Eberhard Karls Universitaet Tuebingen filed Critical Eberhard Karls Universitaet Tuebingen
Publication of EP1740595A1 publication Critical patent/EP1740595A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to new substances, processes for their production, use of these substances and pharmaceutical compositions.
  • Infectious diseases continue to represent a very large medical problem worldwide. Of particular importance here are the increasing resistance of pathogens, particularly bacterial pathogens, which means that these pathogens no longer respond to the currently available drugs. Bacteria that are resistant to a wide range of active substances are also increasingly occurring. This is known as multi-resistant pathogens. Many of the pathogenic multi-resistant Gram-positive bacteria, such as B. the multi-resistant and methicillin-resistant Staphylococcus aureus strains (MRSA) can currently only be treated with glycopeptide antibiotics of the vancomycin / teicoplanin type. It is only a matter of time before multi-tire-resistant, including vancomycin-resistant Staphylococcus aur / s strains will appear in the clinical area. Such super-multi-resistant strains have already been diagnosed in isolated cases and mean death for the infected patient because they cannot be treated.
  • MRSA multi-resistant and methicillin-resistant Staphylococcus aureus strains
  • the object of the invention is therefore to provide new substances which are suitable as active compounds for controlling pathogens, in particular bacterial pathogens, and which can thus be used as new antibiotics.
  • Such new substances should be able to serve as lead structures so that further effective substances can be developed from them.
  • Claims 12 and 13 sum up with appropriate pharmaceutical compositions.
  • Claims 14 to 17 and claim 21 relate to corresponding uses of the substances according to the invention or a method for controlling microorganisms.
  • Claims 22 and 24 are directed to a microorganism, claims 25 and 26 describe suitable processes for producing the substances. Preferred embodiments of these subjects are described in the various dependent claims. The wording of all claims is hereby incorporated by reference into the content of the description.
  • the substance according to the invention is characterized in that it is a polycyclic macrolactone, which can be produced by a representative of the bacterial genus Verrucosispora.
  • This substance is advantageously secreted by the bacterium, i.e. that is, it is released into the culture supernatant when the bacterium is cultivated. It is particularly preferred if this substance develops pharmacological activity and in particular antibiotic activity.
  • the substance according to the invention has this antibiotic effect especially against Gram-positive bacteria.
  • the substance according to the invention has a cytotoxic effect.
  • the inventors were able to obtain preferred embodiments of this substance according to the invention by isolating and characterizing a new bacterial strain from the genus Verrucosispora.
  • This strain hereinafter referred to as AB 18-032
  • This strain was isolated from a marine sediment that was collected from 1000 m depth in Sagami Bay in the Japanese Sea.
  • the strain was deposited with the German Collection of Microorganisms and Cell Cultures GmbH (DSMZ) under DSM No. 15899. Especially before It is therefore important that the substances according to the invention can be produced from the bacterial strain AB 18-032.
  • the bacterial strain AB 18-032 has the following described morphological characteristics.
  • the strain grows as a surface culture on standard complex agar media, such as B. ISP-2 complex medium (0.4% yeast extract, 1% malt extract, 0.4% glucose, 1, 5% agar) as orange-red colonies that turn black after about two weeks of incubation at 27 ° C due to sporulation discolor.
  • 1 shows a scanning electron micrograph of the sporulated substrate mycelium.
  • the chemotaxonomic properties of the strain AB 18-032 are summarized in Table 1.
  • the complete nucleic acid sequence of the gene for the 16S ribosomal RNA was determined by direct sequencing of the PCR-amplified 16S rDNA [Chun, J. & M. Goodfellow (1995), Int. J. Syst. Bacteriol. 45: 240-245; Kim, SB, C. Falkoner, ST Williams & M. Goodfellow (1998), J. Syst. Bacteriol. 48: 59-88]. Then the sequence data was compared with the known sequences from representatives of the subordinate Micromonospo - NEAE. The highest agreement of the sequence from AB 18-032 was found for Verrucosispora gifhornensis with 99.65%.
  • FIG. 2 shows the sequence of the gene for the 16S rRNA of AB 18-032 (SEQ ID No. 1).
  • the strain AB 18-032 could be assigned to the rare actinomycetes genus Verrucosispora. This strain is the first marine representative of this genus and is the second species of this genus described so far in the literature.
  • Verrucosispora gifhornensis 1 DSM strain AB 18-032 44337 Carbon utilization: D (+) xylose ++ D (-) ribose D-fructose -
  • the substances according to the invention are represented by the general formula I.
  • the dotted lines indicate ties that may be present.
  • the numbers indicate the numbering of the carbon atoms in the framework, which was used for the assignment of the 1 H and 13 C chemical shifts in the NMR analysis.
  • Formula I is representative of all conceivable relative configurations and includes all possible stereoisomers.
  • This general formula comprises various substances, that is to say polycyclic macrolactones, which can be used with particular advantage as an active ingredient against microorganisms, in particular against bacteria and / or protozoa.
  • the structure of these substances that is the A-byssomicine, represents a new lead structure on the basis of which the development of new antibiotic substances can be carried out.
  • This embodiment in particular is characterized by particularly advantageous antibiotic properties which have an effect in particular on Gram-positive bacteria.
  • the substance according to formula II is referred to below as abyssomicin B, the substance according to formula III as abyssomicin C and the substance according to formula IV as abyssomicin D.
  • the invention further includes substances which are characterized in that they inhibit the biosynthesis of para-aminobenzoic acid (pABA).
  • these substances according to the invention inhibit the synthesis of para-aminobenzoic acid from chorismic acid.
  • pABA para-aminobenzoic acid
  • these substances according to the invention inhibit the synthesis of para-aminobenzoic acid from chorismic acid.
  • the biosynthetic pathway of para-aminobenzoic acid from chorismic acid is shown on the left-hand side of FIG. 4.
  • Para-aminobenzoic acid is an essential component of folic acid biosynthesis, which is shown on the right-hand side of FIG. 4.
  • the substances according to the invention thus ultimately inhibit the synthesis of folic acid.
  • the particular advantage of this point of attack of the substances according to the invention is that mammals and in particular humans do not have this biosynthetic pathway of folic acid, so that mammalian cells in particular are not adversely affected by the substances according to the invention. Consequently, the substances according to the invention can be used, for example, in the treatment of diseases, in particular infectious diseases, in humans or animals, without having any further side effects. In a particularly preferred embodiment of these substances, these substances have features as described above.
  • the invention includes polycyclic macrolactones as substances which have at least one oxabicyclo system and at least one Michael system as a double bond system as partial structures.
  • the Michael system is preferably a trans double bond that is conjugated to a ketone. It is particularly preferred if this Michael system is located, for example, at positions C7 to C9 of a ring system according to general formula I.
  • a Michael system can advantageously be directly involved in the mechanism of action of the substances according to the invention, for example by advantageously irreversibly interacting with nucleophilic amino acid side chains.
  • the oxabicyclo system contained according to the invention in the polycyclic macrolactones has similarities to the solution conformation of chorismate.
  • the substances according to the invention can therefore to a certain extent mimic the substrate chorismate, so that the special effect of the substances according to the invention can be explained thereby.
  • This oxabicyclo system can be designed, for example, as it results from the formulas I to IV. It is particularly preferred if such a bicyclo system is in the vicinity of the Michael system described. A preferred embodiment of such a substance which has a Michael system and an oxabicyclo system can be described, for example, by the formula III.
  • Substances according to formulas I to IV show an (R) configuration.
  • FIG. 7 B shows examples of the substances according to the invention in a corresponding configuration
  • the formulas shown here correspond to formulas II, II) and IV from left to right.
  • the invention comprises substances which are characterized in that they are derivatives of the polycyclic macrolactones described above.
  • These substances can be naturally occurring substances.
  • this also includes substances that are at least partially produced synthetically or by other means and can be derived, for example, from naturally occurring substances.
  • the substances described above can be used as lead structures in order to design and produce correspondingly suitable substances which may have further advantages over the starting substances.
  • These can advantageously be antibiotically active substances which have similar or improved antibiotic activity as the starting substance, but which, for example, have better properties than the starting substances with regard to side effects in an organism or bioavailability in an organism.
  • the invention comprises pharmaceutical compositions which have at least one substance as described above and at least one pharmaceutically acceptable carrier.
  • the invention encompasses pharmaceutical compositions which, in addition to at least one pharmaceutically acceptable carrier, comprise at least one substance which inhibits the biosynthesis of para-aminobenzoic acid and in particular inhibits the synthesis of para-aminobenzoic acid from chorismic acid.
  • These pharmaceutical compositions can advantageously microorganisms and in particular bacteria and / or protozoa can be combated.
  • compositions can be used particularly advantageously for the treatment of infectious diseases which are caused by bacteria or are at least influenced by bacteria. It is very particularly preferred if these pharmaceutical compositions are used to control gram-positive bacteria. Furthermore, the pharmaceutical compositions are also suitable for the treatment of infectious diseases which are caused or at least influenced by other microorganisms, such as, for example, protozoa. Examples of infectious protozoa that can be controlled with the substances according to the invention are plasmodia, leishmania and trypanosomes, which are responsible for tropical infectious diseases (malaria, leishmaniasis, African sleeping sickness, Chagas disease). The particularly advantageous effect of these pharmaceutical compositions or the corresponding substances is based primarily on the fact that these substances ultimately inhibit the biosynthesis of folic acid.
  • This metabolic pathway is only present in the microorganisms to be controlled, in particular bacteria and / or protozoa, and not in animals or humans, which can be treated with these compositions. It can be used to combat clinically pathogenic microorganisms, in particular pathogenic multiresistant bacteria, which no longer respond to conventional antibiotics.
  • the pharmaceutical compositions are very advantageously suitable for the treatment of infectious diseases which are at least influenced by Gram-positive bacteria.
  • MRSA methicillin-resistant Staphylococcus aureus strains
  • Infectious diseases can also be treated, for example in which Staphylococcus aureus strains are involved which, in addition to various other resistances, are also resistant to vancomycin.
  • Treatment with the pharmaceutical compositions according to the invention can, in particular in such a case, save the patient from death, since there is otherwise no therapeutic option for such super-multi-resistant strains.
  • the pharmaceutical compositions can also be used to combat pathogenic microorganisms which have developed little or no resistance to conventional antibiotics.
  • the invention also encompasses the use of the substances described above for the treatment of infectious diseases which are at least also influenced by bacteria and / or protozoa. Furthermore, the invention includes a use of the substances according to the invention for the manufacture of a medicament for the treatment of infectious diseases which are at least also influenced by bacteria and / or protozoa. The invention also encompasses the use of substances for the treatment of the infectious diseases mentioned, the substances inhibiting the synthesis of para-aminobenzoic acid and in particular inhibiting the synthesis of para-aminobenzoic acid from chorismic acid. The use of appropriate substances for the manufacture of a medicament for the treatment of infectious diseases which are at least influenced by bacteria and / or protozoa is also included.
  • the invention further comprises a method for the treatment of infectious diseases which are at least influenced by bacteria and / or protozoa, at least one substance being administered in the form of a pharmaceutical composition according to the above description.
  • infectious diseases which are at least influenced by bacteria and / or protozoa
  • the invention comprises a method for controlling microorganisms, in particular bacteria and / or protozoa, at least one of the substances according to the invention described above being used.
  • Such a control of microorganisms can be, for example, a disinfection process.
  • surfaces of all kinds, such as surfaces of surgical equipment or furnishings be sterilized to prevent infection with pathogenic microorganisms.
  • the substances according to the invention can be used very advantageously in this context; this is particularly preferably done in combination with other disinfectants.
  • the invention further comprises a microorganism which is characterized in that it can produce at least one substance as described above.
  • the microorganism is a bacterium, this bacterium preferably being a representative of the Verrucosispora genus. It is particularly preferred that this is the bacterial strain AB 18-032 (DSM 15899).
  • the bacterial strain AB 18-032 is the strain from which the inventors were able to isolate the substances listed as examples. Mutants of these microorganisms and in particular of the AB 18-032 strain are also encompassed by the invention.
  • the invention also encompasses other microorganisms which produce corresponding substances.
  • the invention comprises a method for producing at least one substance according to the invention, in which case a microorganism is first cultivated which is capable of producing at least one of the substances described.
  • the substance is preferably secreted by the microorganism, so that in a next process step a filtrate of the culture supernatant is produced in which the desired substance is located.
  • This culture filtrate or the culture supernatant can be used directly in order to use the substances according to the invention accordingly.
  • the substances can also be isolated from the culture filtrate or the culture supernatant and preferably more or less purified so as to have the substance available in a purified form.
  • This is particularly advantageous for medical applications, since if possible only purified substances should be used for pharmaceutical use in order to avoid undesirable effects of other substances.
  • the substance is not secreted, but remains within the microorganism.
  • the substance is isolated from the cultivated microorganisms by suitable methods known to those skilled in the art.
  • the AB 18-032 strain is advantageously used as the microorganism.
  • the microorganism is preferably cultivated in the presence of a medium which contains at least one carbon source, nitrogen source and mineral salts.
  • Subsequent extraction of the substances is preferably carried out from the culture filtrate, but can also take place directly from the culture supernatant.
  • the substances can be isolated from the culture filtrate or the supernatant, for example, by solvent extraction (e.g. ethyl acetate).
  • solvent extraction e.g. ethyl acetate
  • Another possibility is, for example, a sauce Linear chromatography with a polystyrene resin (e.g. Amberlite XAD-16).
  • Further isolation or purification can be carried out by separating the various substances by, for example, absorption and / or exclusion chromatography.
  • the substances can be obtained in pure form by crystallization. If necessary, the purified substances can be further implemented using common chemical processes. Details of this manufacturing process will be readily apparent to those skilled in the art.
  • FIG. 7 (A) diaxial conformation of chorismate in aqueous solution; (B) Configuration structural formulas of the substances according to Form II, III and IV.
  • Inhibitors of chorismic acid biosynthesis and the biosynthetic pathways that are derived from chorismic acid are determined using a so-called cross test, which is based on a modified agar diffusion test. Bacillus subtilis is used as the test organism and is poured into a chemically defined agar medium. One filter paper strip of the cross test batch is soaked with a cell extract, the second filter paper strip with the following variation: (a) Tyr + Phe + Trp + pABA, (b) Tyr + Phe, (c) Trp and (d) pABA.
  • the pattern of the abolition of the individual variants can be used to decide whether it is an inhibitor of early aromatic biosynthesis (before chorismic acid) or an inhibitor that intervenes after chorismic acid, and whether this is an inhibitor of tyrosine (Tyr) / phenylalanine (Phe) biosynthesis, tryptophan (Trp) biosynthesis or para-aminobenzoic acid (pABA) biosynthesis is.
  • Tyr tyrosine
  • Phe phenylalanine
  • Trp tryptophan
  • pABA para-aminobenzoic acid
  • the polycyclic macrolactones are produced by the AB 18-032 strain during the logarithmic to the stationary growth phase.
  • a typical fermentation proceeds as follows: A 10 liter leaf fermenter is mixed with 9.5 liters of complex medium (1% glucose, 1% starch, 1% glycerin, 0.25% Com Steep Powder, 0.5% peptone, 0.2% yeast extract, 0.1% NaCl, 0.3% CaC0 3 ; pH 7.3) filled. The fermenter is inoculated with 5% by volume of a 48-hour shake culture (500 ml Erlenmeyer flask with a side puncture, 100 ml complex medium, 120 rpm, 27 ° C.).
  • the fermenter is incubated at 27 ° C, a speed of 200 rpm and aeration of 0.5 vvm for 4-5 days.
  • the polycyclic macrolactones can be detected in the culture supernatant using HPLC diode array detection (HPLC-DAD) and biological testing.
  • HPLC-DAD HPLC diode array detection
  • the fermenter broth is separated into biomass and culture filtrate with the addition of 2% filter aid (Hyphlo-Supercel). The biomass is discarded.
  • the culture filtrate is adjusted to pH 4 (HCl) and extracted twice with a V * volume of ethyl acetate.
  • the organic phases are combined and concentrated to an oily residue on a vacuum rotary evaporator. The oily residue is washed twice with a small volume of petro- Leum petrol extracted to remove fats. The petroleum spirit extract is discarded.
  • the oily residue is dissolved in a little methanol and separated into the individual raw substance fractions on a Sephadex LH-20 column (100 ⁇ 5 cm) in methanol.
  • Pure polycyclic macrolactones are isolated by low-pressure chromatography on a LiChroprep diol column (40 x 2.6 cm) and a linear gradient from dichloromethane to dichloromethane / methanol (90 + 10) in 3 hours with a flow of 2 ml / min, and a subsequent exclusion chromatography on a Fractogel TSK HW 40 column (90 x 2.5 cm) in methanol at a flow of 0.5 ml / min.
  • ESI-FTICR-MS The mass spectra were recorded on an APEX II FTICR mass spectrometer (4.7 T; Bruker-Daltonics). PEG 400 was used for internal calibration.
  • the isolated substances showed the following physico-chemical properties:
  • Abyssomicin C shows an antibiotic effect in the agar diffusion test, which is directed primarily against the Gram-positive bacteria tested.
  • the gram-negative bacteria and fungi tested were opposite insensitive to the abyssomicins.
  • the antibiotic spectrum of activity is shown in Table 6.
  • the minimum inhibitory concentration (MIC) of Abyssomicin C was determined in a dilution series test. The results are shown in Table 7. As expected, the test germs are much more sensitive to abyssomicin C in a chemically defined medium. Table 7: Minimum inhibitory concentration (MIC; ⁇ g / ml) of Abyssomicin C in the dilution series test (2 ml test tube scale, shaking machine 120 rpm)
  • the determination of the MIC against clinically pathogenic Staphylococcus at / ret / s strains was carried out in a microtiter plate assay.
  • the efficacy of abyssomicin C against the multidrug-resistant, including methicillin-resistant strain S. aureus N315 and against the multidrug-resistant, including vancomycin-resistant strain S. aureus Mu50 was determined. The results are shown in Fig. 6.

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  • Bioinformatics & Cheminformatics (AREA)
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Abstract

La présente invention concerne de nouveaux macrolactones polycyliques qui peuvent être produites en particulier par un représentant de l'espèce bactérienne Verrucosispora. Ces substances se caractérisent de préférence par leur action pharmacologique. Elles ont en particulier une action antibiotique. De préférence, cette action antibiotique s'effectue vis-à-vis de bactéries Gram-positives.
EP04765521A 2003-10-01 2004-09-23 Macrolactones polycyliques Withdrawn EP1740595A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10347472 2003-10-01
DE10353300A DE10353300A1 (de) 2003-10-01 2003-11-11 Polyzyklische Makrolactone
PCT/EP2004/010661 WO2005033114A1 (fr) 2003-10-01 2004-09-23 Macrolactones polycyliques

Publications (1)

Publication Number Publication Date
EP1740595A1 true EP1740595A1 (fr) 2007-01-10

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EP04765521A Withdrawn EP1740595A1 (fr) 2003-10-01 2004-09-23 Macrolactones polycyliques

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US (1) US20080132565A1 (fr)
EP (1) EP1740595A1 (fr)
WO (1) WO2005033114A1 (fr)

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CN102417919B (zh) * 2011-09-02 2017-05-24 山东鲁抗医药股份有限公司 一种发酵法生产高纯度替考拉宁的方法

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Publication number Priority date Publication date Assignee Title
US4255564A (en) * 1977-03-09 1981-03-10 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Novel macrolactone derivatives and process of producing them
FR2674539B1 (fr) * 1991-03-28 1993-05-21 Rhone Poulenc Rorer Sa Procede de preparation enzymatique de macrolactone.

Non-Patent Citations (1)

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Title
See references of WO2005033114A1 *

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WO2005033114A1 (fr) 2005-04-14

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