WO2011111738A1 - Nouvelle substance fki-4429 et méthode pour sa production - Google Patents

Nouvelle substance fki-4429 et méthode pour sa production Download PDF

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WO2011111738A1
WO2011111738A1 PCT/JP2011/055499 JP2011055499W WO2011111738A1 WO 2011111738 A1 WO2011111738 A1 WO 2011111738A1 JP 2011055499 W JP2011055499 W JP 2011055499W WO 2011111738 A1 WO2011111738 A1 WO 2011111738A1
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fki
substance
following formula
represented
culture
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Japanese (ja)
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智 大村
正人 岩月
碌郎 増間
健一 野中
剛 山本
秀明 花木
和朗 塩見
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学校法人北里研究所
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • 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
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal 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
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
    • 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
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
    • 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
    • C12R2001/645—Fungi ; Processes using fungi
    • C12R2001/80—Penicillium

Definitions

  • the present invention relates to a novel FKI-4429 substance that enhances its effect when used in combination with an aminoglycoside antibiotic used as an antibacterial agent, and a method for producing the same.
  • MRSA methicillin-resistant Staphylococcus aureus
  • This pathogenic bacterium has resistance to various drugs such as ⁇ -lactam antibiotics.
  • antibiotics such as glycopeptide vancomycin and aminoglycoside arbekacin are used to treat MRSA infections.
  • particularly resistant bacteria to aminoglycoside antibiotics frequently used for acute treatment have emerged.
  • substances that have the effect of restoring the efficacy of aminoglycoside antibiotics have been reported to cope with such a situation.
  • novel FKI-4429 substance has an action of enhancing the antibacterial activity of streptomycin, kanamycin, dibekacin, arbekacin and the like belonging to aminoglycoside antibiotics. Therefore, it is expected that the novel FKI-4429 substance can be applied to combination therapy with antibacterial agents including aminoglycoside antibiotics.
  • the novel FKI-4429 substance is clearly distinguished in molecular formula and chemical structure from tropolone compounds.
  • Drugs that enhance the activity of aminoglycoside antibiotics are expected to reduce the frequency of resistant bacteria by reducing the dose of aminoglycoside antibiotics and shortening the administration period. At the same time, it is expected to overcome resistance to aminoglycoside antibiotics by using two drugs having different actions in combination.
  • providing a substance having an activity of enhancing the activity of aminoglycoside antibiotics against MRSA provides a new therapeutic agent for MRSA infections and infections caused by multidrug resistant bacteria including resistance to aminoglycoside antibiotics. It is something that is expected and highly expected.
  • FKI-4429 As a result of searching for a substance that overcomes the resistance to MRSA of arbekacin, which is an aminoglycoside antibiotic, targeting metabolites produced by microorganisms, the present inventors have found that the newly cultured filamentous fungus FKI-4429 was isolated from soil. It was found that a substance having an action to overcome arbekacin resistance was produced. Subsequently, the culture was purified and isolated, and as a result, four types of substances, FKI-4429-1, FKI-4429-2, FKI-4429-3, and FKI-4429-4, which have an action to overcome resistance to arbekacin, were obtained. A compound was obtained. Hereinafter, these are collectively referred to as FKI-4429 substances.
  • the FKI-4429 substance is at least one of FKI-4429-1, FKI-4429-2 substance, FKI-4429-3 substance, and FKI-4429-4 substance.
  • a substance having a chemical structure such as the FKI-4429 substance has not been known at all.
  • the present invention also includes an FKI-4429-1 substance represented by the formula [I] and an FKI-4429- represented by the formula [II], which belongs to a filamentous fungus as described in the claim 5.
  • Ability to produce FKI-4429 substance which is at least one of two substances, FKI-4429-3 substance represented by formula [III] and FKI-4429-4 substance represented by formula [IV]
  • the present invention also provides that the microorganism is Penicillium sp. FKI-4429 (accession number (domestic deposit) NITE P-869, accession number (international deposit), as described in claim 6. 6. The manufacturing method according to claim 5, which is NITE BP-869).
  • the present invention further includes Penicillium sp. FKI-4429 (Accession number (domestic deposit) NITE P-869, Accession number (international deposit) NITE BP-869), as described in claim 7. Is a stock.
  • the antibacterial agent of the present invention comprises FKI-4429-1 substance represented by the formula [I] and FKI-4429-2 substance represented by the formula [II]. And an FKI-4429-3 substance represented by the formula [III] and an FKI-4429-4 substance represented by the formula [IV], and an aminoglycoside antibiotic.
  • novel FKI-4429-1 substance, novel FKI-4429-2 substance, novel FKI-4429-3 substance and novel FKI-4429-4 substance of the present invention are used in combination with an aminoglycoside antibiotic used as an antibacterial agent This enhances the activity of aminoglycoside antibiotics. Further, according to the production method of the present invention, a novel FKI-4429-1 substance, a novel FKI-4429-2 substance, a novel FKI-4429-3 substance, and a novel FKI-4429-4 substance can be produced.
  • FIG. 1 shows an ultraviolet absorption spectrum (in a methanol solution) of the FKI-4429-1 substance according to the present invention.
  • 2 shows an infrared absorption spectrum (potassium bromide method) of the FKI-4429-1 substance according to the present invention.
  • 2 shows a proton nuclear magnetic resonance spectrum (in CD 3 OH) of the FKI-4429-1 substance according to the present invention.
  • 2 shows a carbon nuclear magnetic resonance spectrum (in CD 3 OH) of the FKI-4429-1 substance according to the present invention.
  • 2 shows an ultraviolet absorption spectrum (in a methanol solution) of the FKI-4429-2 substance according to the present invention.
  • FIG. 3 shows an infrared absorption spectrum (potassium bromide method) of FKI-4429-2 substance according to the present invention.
  • FIG. 2 shows a proton nuclear magnetic resonance spectrum (in CD 3 OH) of substance FKI-4429-2 according to the present invention.
  • 3 shows a carbon nuclear magnetic resonance spectrum (in CD 3 OH) of the FKI-4429-2 substance according to the present invention.
  • 2 shows an ultraviolet absorption spectrum (in a methanol solution) of the FKI-4429-3 substance according to the present invention.
  • FIG. 3 shows an infrared absorption spectrum (potassium bromide method) of FKI-4429-3 substance according to the present invention.
  • FIG. 2 shows a proton nuclear magnetic resonance spectrum (in CD 3 OD) of FKI-4429-3 substance according to the present invention.
  • FIG. 2 shows a carbon nuclear magnetic resonance spectrum (in CD 3 OD) of the FKI-4429-3 substance according to the present invention.
  • 2 shows an ultraviolet absorption spectrum (in a methanol solution) of the FKI-4429-4 substance according to the present invention.
  • FIG. 3 shows an infrared absorption spectrum (potassium bromide method) of FKI-4429-4 substance according to the present invention.
  • FIG. 2 shows a proton nuclear magnetic resonance spectrum (in CD 3 OD) of substance FKI-4429-4 according to the present invention.
  • FIG. 2 shows a carbon nuclear magnetic resonance spectrum (in CD 3 OD) of FKI-4429-4 substance according to the present invention.
  • the FKI-4429 substance of the present invention can be obtained by a conventional method from a culture obtained by culturing a microorganism having the ability to produce an FKI-4429 substance belonging to a filamentous fungus and accumulating the FKI-4429 substance.
  • the FKI-4429 substance is represented by the above formulas [I], [II], [III], and [IV].
  • strains that can be used in the present invention all FKI-4429 substance-producing bacteria belonging to filamentous fungi can be used.
  • Penicillium sp. FKI-4429 strain newly isolated from soil by the present inventors can be mentioned.
  • the conidial pattern (50-125 ⁇ 1.5-2.5 ⁇ m) occurred upright from the aerial hyphae and did not branch.
  • Penicillus is formed at the tip of the conidial pattern.
  • Penicills are two-wheelers and are composed of 3-5 fierides.
  • the phialide was cylindrical and had a size of 10.0 to 12.5 ⁇ 2.3 to 2.7 ⁇ m.
  • Fiaro-type conidia are formed from the tip of the phialide and become chained as the culture time elapses. The conidia were spindle-shaped, green, 2.5-5.0 ⁇ 2.3-2.7 ⁇ m in size, and the surface was rough.
  • Table 1 shows the results of macroscopic observation when cultured on various agar media at 25 ° C for 7 days.
  • Optimal growth conditions The optimal growth conditions for this strain are pH 3-7 and temperature 26.1-36.9 ° C. 2) Growth range The growth range of this strain is pH 2-9 and temperature 10.2-38.6 ° C. 3) Distinguishing between aerobic and anaerobic aerobic.
  • This strain is an independent administrative agency located in 2-5-8 Kazusa Kamashi, Kisarazu City, Chiba Prefecture, Japan (zip code 292-0818) based on the Budapest Treaty concerning the international recognition of deposits of microorganisms under patent procedures.
  • the product was transferred to the International Depositary on January 17, 2011, to the Patent Microorganism Depositary Center for Product Evaluation Technology.
  • the deposit number (international deposit) is NITE BP-869.
  • the FKI-4429 substance belongs to a filamentous fungus, and can be obtained by culturing a microorganism capable of producing the FKI-4429 substance. Culturing is performed according to the culture method of general microorganisms.
  • any nutrient source that can be used as a nutrient source for filamentous fungi may be used.
  • a nutrient source for filamentous fungi for example, commercially available peptone, meat extract, corn steep liquor, cotton seed flour, peanut flour, soybean flour, yeast extract, NZ-amine, casein hydrate, nitrogen sources such as sodium nitrate, ammonium nitrate, ammonium sulfate, glycerin
  • carbohydrates such as starch, glucose, galactose and mannose, carbon sources such as fat, and inorganic salts such as sodium chloride, phosphate, calcium carbonate and magnesium sulfate can be used alone or in combination.
  • metal salts and vegetation / planting / mineral oil can be added as an antifoaming agent as necessary. Any of these may be used as long as they are used by the producing bacteria and serve to produce the FKI-4429 substance, and all known filamentous fungal culture materials can be used.
  • Liquid culture is preferable for mass culture of the FKI-4429 substance, and the culture temperature can be applied within the range in which the producing bacteria can grow and the FKI-4429 substance can be produced.
  • the culture can be appropriately selected according to the properties of the FKI-4429 substance-producing bacterium using the conditions described above.
  • the FKI-4429 substance can be extracted from the culture solution with a water-immiscible organic solvent such as chloroform or ethyl acetate.
  • a water-immiscible organic solvent such as chloroform or ethyl acetate.
  • known methods used for collecting fat-soluble substances such as adsorption chromatography, gel filtration chromatography, scraping from thin layer chromatography, centrifugal countercurrent distribution chromatography, high performance liquid chromatography, etc. These can be collected purely by appropriately combining or repeating.
  • ⁇ max is 3435, 2956, 2925, 2857, 1743, A characteristic absorption maximum is shown at 1641, 1446 cm ⁇ 1 and the like.
  • Solubility in solvents soluble in methanol, ethyl acetate and chloroform. Insoluble in water and hexane.
  • Proton and carbon nuclear magnetic resonance spectra 1 H-NMR spectrum and 13 C-NMR spectrum: Hydrogen chemical shift (ppm) measured in CD 3 OH with a Varian 400 and 100 MHz nuclear magnetic resonance spectrometer And the chemical shift (ppm) of carbon is as shown below. The number in parentheses indicates the number of hydrogen.
  • FKI-4429-1 substance was determined to have a chemical structure represented by the following formula [I].
  • Substance FKI-4429-2 (1) Property: white powder (2) Molecular formula: C 19 H 30 O 5 HR-ESI-MS (m / z) [M + Na] + calculated value 361.1991, actual value 361.1985 (3) Molecular weight: 338 Observation of [M + Na] + 361 by ESI-MS (m / z) (4) Ultraviolet absorption spectrum: the ultraviolet absorption spectrum measured in a methanol solution is as shown in FIG. 5, and ⁇ max ( ⁇ ): 214 nm The absorption maximum of (25200) is shown. (5) Infrared absorption spectrum: The infrared absorption spectrum measured by the potassium bromide tablet method is as shown in FIG.
  • ⁇ max is 3444, 2956, 2925, 2858, 1751, 1685, 1633, 1446 cm ⁇ 1.
  • the characteristic absorption maximum is shown.
  • Solubility in solvents soluble in methanol, ethyl acetate and chloroform. Insoluble in water and hexane.
  • Proton and carbon nuclear magnetic resonance spectra Hydrogen chemical shift (ppm) and carbon chemical shift (ppm) measured with Varian 400 and 100 MHz nuclear magnetic resonance spectrometer in CD 3 OH are as shown below. It is. The number in parentheses indicates the number of hydrogen.
  • FKI-4429-2 substance was determined to have a chemical structure represented by the following formula [II].
  • ⁇ max is 3429, 2956, 2925, 2858, 1758, 1705, 1647 cm ⁇ 1 and the like. It shows a characteristic absorption maximum.
  • Solubility in solvents Soluble in methanol, ethyl acetate and chloroform. Insoluble in water and hexane.
  • Proton and carbon nuclear magnetic resonance spectrum The chemical shift (ppm) of hydrogen and the chemical shift (ppm) of carbon measured by Varian 400 and 100 MHz nuclear magnetic resonance spectrometer in CD 3 OD are as shown below. It is. The number in parentheses indicates the number of hydrogen.
  • FKI-4429-4 substance (1) Property: white powder (2) Molecular formula: C 19 H 28 O 5 HR-FAB-MS (m / z) [M + H] + calculated value 337.1956, actual value 337.1986 (3) Molecular weight: 336 Observation of [M + H] + 337 by FAB-MS (m / z) (4) Ultraviolet absorption spectrum: the ultraviolet absorption spectrum measured in a methanol solution is as shown in FIG. 13, and ⁇ max ( ⁇ ): 202 nm (67000), 258 nm (6980) absorption maximum. (5) Infrared absorption spectrum: The infrared absorption spectrum measured by the potassium bromide tablet method is as shown in FIG.
  • ⁇ max is 3452, 2956, 2925, 2857, 1703, 1639, 1457, 1380 cm ⁇ 1.
  • the characteristic absorption maximum is shown.
  • Solubility in solvents soluble in methanol, ethyl acetate and chloroform. Insoluble in water and hexane.
  • Proton and carbon nuclear magnetic resonance spectrum The chemical shift (ppm) of hydrogen and the chemical shift (ppm) of carbon measured by Varian 400 and 100 MHz nuclear magnetic resonance spectrometer in CD 3 OD are as shown below. It is. The number in parentheses indicates the number of hydrogen.
  • Agar slope medium is glycerol 0.1% (Wako Pure Chemical Industries), potassium dihydrogen phosphate 0.08% (Kanto Chemical), dipotassium hydrogen phosphate 0.02% (Kanto Chemical), magnesium sulfate heptahydrate 0.02% (Wako Pure Chemical), Potassium chloride 0.02% (Kanto Chemical), Sodium nitrate 0.2% (Wako Pure Chemical), Yeast extract 0.02% (Oriental yeast), Agar 1.5% ( Fresh water food) and adjusted to pH 6.0.
  • the seed medium is glucose 2.0% (Wako Pure Chemical Industries), yeast extract 0.2% (Oriental yeast), magnesium sulfate heptahydrate 0.05% (Wako Pure Chemical Industries), polypeptone 0.5% (Wako Pure Chemical Industries, Ltd.) ), Potassium dihydrogen phosphate 0.1% (Kanto Chemical), agar 0.1% (Shimizu Foods) and adjusted to pH 6.0. Thereafter, 1% each of the cells was inoculated into four 500 mL Erlenmeyer flasks containing 100 mL of production medium, and cultured on a rotary shaker at 27 ° C. and 210 rpm for 6 days.
  • the production medium is water-soluble starch 3.0% (Hokuren), glycerol 1.0% (Wako Pure Chemicals), Soybean Meal 2.0% (Tokyo Preserved Food), dry yeast 0.3% (Oriental Yeast), chloride Potassium 0.3% (Kanto Chemical), Magnesium sulfate heptahydrate 0.05% (Wako Pure Chemical), Calcium carbonate 0.2% (Kanto Chemical), Dipotassium hydrogen phosphate 0.05% (Kanto Chemical) And adjusted to pH 7.0.
  • the antibacterial activity on each medium against the test bacteria was measured by measuring the diameter of the inhibition circle diameter after culturing at 35 ° C. for 20 hours by the paper disc method (diameter 6 mm, thin: Advantec).
  • the measured inhibition circle diameter was expressed in unit mm and shown in Table 2.
  • no inhibition circle was observed for FKI-4429-1, 2, 3 and 4 under the conditions of 30, 10, 3 and 0.3 ⁇ g / disk, respectively, in the absence of arbekacin.
  • a blocking circle having a diameter of 8 mm to 13 mm was observed in all, confirming the arbekacin activity enhancing action.
  • “NT” indicates that the test was not performed.
  • the FKI-4429 substance was evaluated for its ability to overcome arbekacin resistance against MRSA TH-1466 strain according to a micro liquid dilution method. Evaluation was carried out by partially modifying the standard method of the Japanese Society for Chemotherapy (Chemotherapie 38, 103-105, 1990). After adding 85 ⁇ L of Mueller-Hinton broth (2.1% w / v) to each well of 96 well plate (Corning, USA), arbekacin previously diluted serially with sterilized water was 4.8. 5 ⁇ L was added to each well so as to be from ⁇ 10 ⁇ 4 to 256 ⁇ g / mL.
  • Table 3 shows the MICs when arbekacin and FKI-4429 were used in combination.
  • the MIC When arbekacin alone was used, the MIC was 128 ⁇ g / mL, but when the FKI-4429 substance was used in combination, the MIC decreased to a maximum of 4 ⁇ g / mL, confirming a 32-fold increase in activity.
  • a microorganism represented by the strain FKI-4429 belonging to the genus Penicillium having the ability to produce a novel FKI-4429 substance is cultured in a medium, and the FKI-4429 substance collected from the culture solution is an antibacterial agent. Because it has the effect of enhancing its effect by using in combination with aminoglycoside antibiotics that have been used as methicillin-resistant Staphylococcus aureus (MRSA) infection and multidrug-resistant bacteria including aminoglycoside antibiotic resistance It is expected to be useful as a therapeutic agent for infectious diseases.
  • MRSA methicillin-resistant Staphylococcus aureus

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Abstract

On divulgue une substance FKI-4429-1 représentée par la formule [I] et trois autres substances. Des bactéries filamenteuses présentant l'aptitude à produire cette substance FKI-4429-1 sont cultivées dans un milieu. La substance FKI-4429-1 s'accumule dans cette culture. La substance FKI-4429-1 est collectée à partir de cette culture. Les trois autres substances sont la substance FKI-4429-2, la substance FKI-4429-3 et la substance FKI-4429-4. Un médicament antibactérien contient la substance FKI-4429-1 et un antibiotique aminoglycosidique.
PCT/JP2011/055499 2010-03-10 2011-03-09 Nouvelle substance fki-4429 et méthode pour sa production WO2011111738A1 (fr)

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ALLEN N.E. ET AL.: "7-Hydroxytropolone: an inhibitor of aminoglycoside-2"-O- adenylyltransferase.", ANTIMICROB AGENTS CHEMOTHER., vol. 22, 1982, pages 824 - 831 *

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