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WO2006075395A1 - RENFORCATEUR D'ACTIVITE D'ANTIBIOTIQUE A BASE DE β-LACTAME ET PROCEDE POUR LE PRODUIRE - Google Patents

RENFORCATEUR D'ACTIVITE D'ANTIBIOTIQUE A BASE DE β-LACTAME ET PROCEDE POUR LE PRODUIRE Download PDF

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Publication number
WO2006075395A1
WO2006075395A1 PCT/JP2005/000447 JP2005000447W WO2006075395A1 WO 2006075395 A1 WO2006075395 A1 WO 2006075395A1 JP 2005000447 W JP2005000447 W JP 2005000447W WO 2006075395 A1 WO2006075395 A1 WO 2006075395A1
Authority
WO
WIPO (PCT)
Prior art keywords
substance
activity
producing
culture
activity enhancer
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.)
Ceased
Application number
PCT/JP2005/000447
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English (en)
Japanese (ja)
Inventor
Hiroshi Tomoda
Rokuro Masuma
Satoshi Omura
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.)
Kitasato Institute
Original Assignee
Kitasato Institute
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
Application filed by Kitasato Institute filed Critical Kitasato Institute
Priority to PCT/JP2005/000447 priority Critical patent/WO2006075395A1/fr
Publication of WO2006075395A1 publication Critical patent/WO2006075395A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • 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
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention is effective when used in combination with S-lactam antibiotics used as an antibacterial agent for the treatment of MRS epilepsy infection in animals, including humans, such as the powerful rubapenem imipenem.
  • the present invention relates to a lactam antibiotic activity enhancer and a method for producing the same. Background art
  • MRSA methicillin-resistant Staphylococcus aureus
  • S-lactam antibiotics such as venams such as cloxacillin, cefums such as cefazolin, and strong rubapenems such as imibenem, panipenem, and meropenem.
  • antibiotics such as the glycopeptide vancomycin and the aminoglycoside arbekacin, which have not been reported to be resistant at present, are used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. .
  • This compound contains FK 1-1 938 A substance and / or FK 1— 1 9 38 B substance and / or FK I-1 938 ⁇ 'substance and / or FK I— 1 9 38 C substance (collectively FK 1- 1) (named 938 substance) was confirmed to have the activity-enhancing action of azole antifungal agents, and an international application was filed as PCTZJP 2004/0 1 638 1.
  • ⁇ -Lactam antibiotics and other drugs that enhance the activity of rubipenem imipenem may be useful in the treatment of MRSA infections.
  • a drug that enhances the activity of ⁇ -lactam antibiotics is expected to reduce the dose of ⁇ -lactam antibiotics, shorten the administration period, and reduce the frequency of resistant bacteria.
  • it is expected to overcome resistance to ⁇ -lactam antibiotics by combining two drugs with different actions.
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSA methicillin-resistant Staphylococcus aureus
  • the present invention has an action of enhancing the activity of antibacterial agents currently in practical use, and acts on MRS A infection at a low concentration and in a short period of time, thereby reducing the appearance frequency of resistant bacteria.
  • An object of the present invention is to provide a potentiating agent capable of enhancing the activity of ⁇ -latata antibiotics and a method for producing the same.
  • the present invention provides an activity enhancer that enhances the activity of a 3-lactam antibiotic, characterized by using the FK 1-1 938 A substance represented by the formula:
  • the present invention provides an activity enhancer in which the ⁇ -lactam antibiotic is selected from the group consisting of penams, cefums, and carpapenems.
  • FK 1-1 938 A substance represented by the above formula [I] is combined with / 3-lactam antibiotic, and has a synergistic effect on MR SA.
  • An activity enhancer is provided.
  • the present invention belongs to Penicillium citrinum, and a microorganism having the ability to produce the FK 1-1 938 A substance represented by the aforementioned formula [I] is cultured in a medium, and the FK I-1 938 A substance is contained in the culture. And a method for producing an activity enhancer that collects FK 1-1 938 A substance that enhances the activity of S-lactam antibiotics from the culture Is.
  • the present invention provides a method for producing an activity enhancer wherein the lactam antibiotic is selected from the group consisting of penams, cephems and carpapenems.
  • the present invention belongs to Penicillium citrinum, and Penicillium citrinum having the ability to produce FK 1-1 938 A substance represented by the above-mentioned formula [I] (Pen ici I li um citri num) FK I-1 938 (FERM ABP-1 0 1 49) or a mutant thereof.
  • the present invention provides a method for producing an enhancer having an activity enhancing action of ⁇ -lactam antibiotics.
  • the present invention provides Benicillium Citrinum FK I-1 938 (FERM ABP-1 0 149).
  • Microorganisms capable of producing FKI-1 938 A substance having activity enhancing action of / S-lactam antibiotic represented by the above formula [I] (hereinafter referred to as “FK I-1 938 substance producing bacteria”) Is belonging to Penicillium citrinum, but is not particularly limited as long as it has the ability to produce the substance of the present invention (yS-lactam antibiotic activity enhancer).
  • FK I-1 938 substance producing bacteria Is belonging to Penicillium citrinum, but is not particularly limited as long as it has the ability to produce the substance of the present invention (yS-lactam antibiotic activity enhancer).
  • Penicillium citrinum P en icilli um citrin um
  • the bacteriological properties of this strain are as follows.
  • This strain grew well on the lapec yeast extract agar medium, 25% glycerin 'nitrate agar medium, wort agar medium, Miura agar medium, etc., and conidia were well established on various agar mediums.
  • Fia mouth-type conidia are formed from the tip of the phialide and become chained as the culture time elapses. Conidia were spherical to subspherical, blue-green, size 2.3 to 3.0 / m, and the surface was smooth.
  • the optimal growth conditions for this strain are pH 4-8, temperature 14.48-30.6 ° C.
  • the growth range of this strain is pH 3 to 10 and temperature 7.5 to 32.4 ° C.
  • Penicillium citrinum FK I-1 938 (Penicillium citri num FKI-1 938), based on the Budapest Treaty on the International Approval of Deposit of Microorganisms in Patent Procedures.
  • the FK 1-1 938 substance-producing bacterium used in the present invention the aforementioned Benicillium citrinum FK I-1 938 strain can be mentioned as a preferred example.
  • mycological properties are extremely high. It is easy to mutate, is not constant, and naturally or commonly used UV irradiation, X-ray irradiation, or mutant derivatives such as N-methyl-N'-nitro-1 N-nitrosoguanidine, 2-aminopurine, etc.
  • FK I-1938 substance-producing bacteria belonging to Penicillium citrinum are cultured in a medium.
  • nutrient sources suitable for the production of the above FK I-1 938 A substance carbon sources that can be assimilated by microorganisms, nitrogen sources that can be extinguished, and nutrient media containing inorganic salts, vitamins, etc. as necessary are used. Is done.
  • As the assimilable carbon source glucose, fructose, maltose, lactose, galactose, dextrin, saccharides such as starch, vegetable oils such as soybean oil, etc. may be used alone or in combination.
  • Digestible nitrogen sources include peptone, yeast extract, meat extract, soy flour, cottonseed flour, corn steep liquor, malt extract, casein, amino acid, urea, ammonium salts, and nitrates, either alone or in combination It is done. Others Salts such as phosphate, magnesium salt, calcium salt, sodium salt, potassium salt, heavy metal salts such as iron salt, manganese salt, copper salt, cobalt salt, zinc salt, etc. FK 1-1 938 A suitable for production of substance A is added as appropriate In the cultivation, when foaming is severe, an antifoaming agent such as a surfactant such as liquid paraffin, animal oil, vegetable oil, or silicone may be added as necessary.
  • an antifoaming agent such as a surfactant such as liquid paraffin, animal oil, vegetable oil, or silicone may be added as necessary.
  • the medium may be liquid or solid as long as the nutrient source is contained, but it is usually preferable to use a liquid medium for culture.
  • culture using a flask is preferable.
  • the composition of the medium used for the pre-culture and the medium used for the production culture may be the same, or both may be changed if necessary.
  • the culture temperature can be appropriately changed within the range in which this FKI-1 9 3 8 substance-producing bacterium produces this FK 1-1 9 3 8 A substance, but it is usually 20 to 30 ° C, preferably 2 Incubate before and after 7 ° C.
  • the culture pH is usually 5-8, preferably around 7.
  • the culture time varies depending on the culture conditions, but is usually about 4-7 days.
  • the thus obtained F K I-1 9 3 8 A substance is present in cultured cells and culture filtrate.
  • the whole culture is extracted with a water-miscible organic solvent such as acetone, and the extract is distilled off with an organic solvent under reduced pressure. This is done by extracting the residue with a water-immiscible organic solvent such as ethyl acetate.
  • the physicochemical properties of the FK 1-1 9 3 8 A substance of the present invention are as follows.
  • Red external absorption spectrum Infrared absorption spectra measured by the bromide-powered Rum tablet method are 2 9 6 4, 28 5 9, 1 6 5 4, 1 6 0 4, 1 4 9 8, with a characteristic absorption maximum at 1 4 3 0 cm- 1 ,
  • the biological properties of the FK 1-1 938 A substance of the present invention are as follows.
  • Staphy lococcusa ⁇ reus is a mu eller—Hi nt on broth (2.1% W / Y) (DI FCO) After culturing at 37 ° C for 20 hours, it was suspended in the same medium to a level equivalent to 0.5 Mc F ARAND (approximately 10 8 CFU / mL), and MHA medium (Mu eller— Hintonbroth 2.1% ( w / v) ⁇ Ag ar 1.5%) (1), and imipenem (Japan, Ariyu Pharmaceutical Co., Ltd., Cenamu intramuscular titer 0.5) in the same composition on the growth of test bacteria Inoculated into medium (2) added to give a final concentration of 10 zgZmL, and hereinafter, medium containing imipenem in MHA medium (1) is referred to as MH AI.
  • the bacteria method was smeared on each medium with a sterile cotton swab (Kawamoto Sangyo Co., Ltd., Japan) according to the US National Laboratory Standards Committee (Clinical Laboratories: NCCLS).
  • NCCLS National Laboratory Standards Committee
  • Each culture for test bacteria The antibacterial activity on the ground was expressed by the paper disk method (thin, 6 mm: ADVANTECH) in which 10 g of each compound was impregnated and the diameter of the blocking circle after 20 hours at 37 ° C. was expressed in mm.
  • the results are shown in Table 2 below.
  • Benicillium citrinum FK I-1 938 (Penici 1 1 i um citrin urn FK I-1 938. FERM ABP— 1 0 1 49) grown on an agar medium was inoculated with platinum ears. And inoculated for 72 hours at 27 ° C and used as a seed culture.
  • glycerol 2.0 sucrose 1.0%, ammonium mutate 0.5%, potassium dihydrogen phosphate 0.1%, magnesium sulfate heptahydrate 0.
  • the FK 1-1 938 A substance according to the present invention has the activity of enhancing the activity of / S-lactam antibiotics, particularly impenem. Therefore, it is possible to provide an enhancer with an imipenem activity-enhancing action against methicillin-resistant Staphylococcus aureus (MRSA), including methicillin-resistant Staphylococcus aureus (MRSA) —a multiplicity that includes resistance to lactam antibiotics. It is possible to obtain useful pharmaceuticals that can act at low concentrations and in a short period of time against infectious diseases caused by drug-resistant bacteria and reduce the frequency of resistant bacteria.
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSA methicillin-resistant Staphylococcus aureus

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Zoology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Selon la présente invention, le Penicillium citrinum FKI-1938 (FERM ABP-10165), qui appartient au genre Penicillium citrinum et a la capacité de produire la substance FKI-1938A, est cultivé dans un milieu de culture afin d'accumuler de la substance FKI-1938A dans la culture. On récolte ensuite cette substance FKI-1938A, laquelle renforce l'activité de l’antibiotique à base de β-lactame. La substance obtenue présentant une action d'augmentation de l'activité de l'impenem, elle agit, en faible concentration et sur un court laps de temps, sur les infections à MRSA (staphylocoques dorés résistants à la méthicilline). La fréquence d’apparition de bactéries résistantes est ainsi réduite, tandis qu’une efficacité pour vaincre la résistance est également attendue.
PCT/JP2005/000447 2005-01-11 2005-01-11 RENFORCATEUR D'ACTIVITE D'ANTIBIOTIQUE A BASE DE β-LACTAME ET PROCEDE POUR LE PRODUIRE Ceased WO2006075395A1 (fr)

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PCT/JP2005/000447 WO2006075395A1 (fr) 2005-01-11 2005-01-11 RENFORCATEUR D'ACTIVITE D'ANTIBIOTIQUE A BASE DE β-LACTAME ET PROCEDE POUR LE PRODUIRE

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013082657A (ja) * 2011-10-12 2013-05-09 Kitasato Institute Ｍｒｓａ産生黄色色素の生成阻害能を示す新規化合物とその用途
CN105001228A (zh) * 2015-07-17 2015-10-28 福建省肿瘤医院 源于桔青霉的penicitrinine A在制备抗人口腔表皮样瘤药物中的应用
CN105017272A (zh) * 2015-07-17 2015-11-04 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人乳腺癌药物的应用
CN105061446A (zh) * 2015-07-17 2015-11-18 福建省肿瘤医院 源于桔青霉的penicitrinine A及在制备抗鼻咽癌药物上的应用
CN105061445A (zh) * 2015-07-17 2015-11-18 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人胃癌药物的应用
CN105061443A (zh) * 2015-07-17 2015-11-18 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人肝癌药物的应用
CN105061444A (zh) * 2015-07-17 2015-11-18 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人结直肠癌药物的应用
CN105131006A (zh) * 2015-07-17 2015-12-09 福建省肿瘤医院 源于桔青霉的penicitrinine A及在制备抗恶性黑色素瘤药物上的应用
CN105153175A (zh) * 2015-07-17 2015-12-16 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人食管癌药物的应用
CN105153176A (zh) * 2015-07-17 2015-12-16 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人肺癌药物的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09501702A (ja) * 1994-05-09 1997-02-18 旭化成工業株式会社 増強された抗生物質組成物
JPH09509677A (ja) * 1994-03-04 1997-09-30 ロイヤル フリー ホスピタル スクール オブ メディシン 茶エキスまたはその活性フラクションおよびβ−ラクタム抗生物質を含む抗菌剤
WO1998017625A1 (fr) * 1996-10-22 1998-04-30 Daiichi Pharmaceutical Co., Ltd. Nouveaux remedes pour des maladies infectieuses

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09509677A (ja) * 1994-03-04 1997-09-30 ロイヤル フリー ホスピタル スクール オブ メディシン 茶エキスまたはその活性フラクションおよびβ−ラクタム抗生物質を含む抗菌剤
JPH09501702A (ja) * 1994-05-09 1997-02-18 旭化成工業株式会社 増強された抗生物質組成物
WO1998017625A1 (fr) * 1996-10-22 1998-04-30 Daiichi Pharmaceutical Co., Ltd. Nouveaux remedes pour des maladies infectieuses

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013082657A (ja) * 2011-10-12 2013-05-09 Kitasato Institute Ｍｒｓａ産生黄色色素の生成阻害能を示す新規化合物とその用途
CN105001228A (zh) * 2015-07-17 2015-10-28 福建省肿瘤医院 源于桔青霉的penicitrinine A在制备抗人口腔表皮样瘤药物中的应用
CN105017272A (zh) * 2015-07-17 2015-11-04 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人乳腺癌药物的应用
CN105061446A (zh) * 2015-07-17 2015-11-18 福建省肿瘤医院 源于桔青霉的penicitrinine A及在制备抗鼻咽癌药物上的应用
CN105061445A (zh) * 2015-07-17 2015-11-18 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人胃癌药物的应用
CN105061443A (zh) * 2015-07-17 2015-11-18 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人肝癌药物的应用
CN105061444A (zh) * 2015-07-17 2015-11-18 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人结直肠癌药物的应用
CN105131006A (zh) * 2015-07-17 2015-12-09 福建省肿瘤医院 源于桔青霉的penicitrinine A及在制备抗恶性黑色素瘤药物上的应用
CN105153175A (zh) * 2015-07-17 2015-12-16 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人食管癌药物的应用
CN105153176A (zh) * 2015-07-17 2015-12-16 福建省肿瘤医院 源于桔青霉的penicitrinine A及其制备抗人肺癌药物的应用

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