WO2011111738A1 - Novel fki-4429 substance and method for producing same - Google Patents

Novel fki-4429 substance and method for producing same 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
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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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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • 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
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    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi
    • C12R2001/80—Penicillium

Abstract

Disclosed are substance FKI-4429-1 represented by formula [I] and three other substances. Filamentous bacteria having the capability of producing this substance FKI-4429-1 are cultured in a medium. The substance FKI-4429-1 accumulates in this culture. The substance FKI-4429-1 is collected from this culture. The other three substances are substance FKI-4429-2, substance FKI-4429-3 and substance FKI-4429-4. An antibacterial drug contains substance FKI-4429-1 and an aminoglycoside antibiotic.

Description

新規ＦＫＩ－４４２９物質およびその製造方法Novel FKI-4429 substance and production method thereof
　本発明は、抗菌剤として利用されているアミノグリコシド系抗生物質と併用することによりその効果を増強する新規ＦＫＩ－４４２９物質及びその製造方法に関する。 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.
　近年、メチシリン耐性黄色ブドウ球菌（ＭＲＳＡ）は、院内感染の主な原因菌として社会的問題となっている。この病原菌は、β－ラクタム抗生物質など種々の薬剤に対する耐性を有している。一般にＭＲＳＡ感染症の治療には、グリコペプチド系のバンコマイシンやアミノグリコシド系のアルベカシンといった抗生物質が使用されている。このうち特に急性期の治療に多用されるアミノグリコシド系抗生物質に対する耐性菌が出現している。現在までに、このような状況に対処すべく、アミノグリコシド系抗生物質の効力を回復させる作用を有する物質が報告されている。例えば、アミノグリコシド系抗生物質を含む抗菌剤と組み合わせて使用することで相乗的効果を示す７－ヒドロキシトロポロンがこれに相当する（例えば、非特許文献１参照）。新規ＦＫＩ－４４２９物質は、アミノグリコシド系抗生物質に属するストレプトマイシン、カナマイシン、ジベカシン、アルベカシンなどの抗菌活性を増強する作用を有している。このため、新規ＦＫＩ－４４２９物質は、アミノグリコシド系抗生物質を含む抗菌剤との併用療法へも応用できることが期待される。新規ＦＫＩ－４４２９物質は、トロポロン系化合物とは、分子式および化学構造が明確に区別される。 In recent years, methicillin-resistant Staphylococcus aureus (MRSA) has become a social problem as the main causative agent of nosocomial infections. This pathogenic bacterium has resistance to various drugs such as β-lactam antibiotics. In general, antibiotics such as glycopeptide vancomycin and aminoglycoside arbekacin are used to treat MRSA infections. Among them, particularly resistant bacteria to aminoglycoside antibiotics frequently used for acute treatment have emerged. To date, substances that have the effect of restoring the efficacy of aminoglycoside antibiotics have been reported to cope with such a situation. For example, 7-hydroxytropolone that exhibits a synergistic effect when used in combination with an antibacterial agent including an aminoglycoside antibiotic corresponds to this (for example, see Non-patent Document 1). The 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.
　アミノグリコシド系抗生物質の活性を増強する薬剤は、アミノグリコシド系抗生物質の投与量を減量させ、投与期間を短縮させることにより耐性菌出現の頻度を低減させることが期待される。また同時に、作用の異なる２つの薬剤を併用することにより、アミノグリコシド系抗生物質に対する耐性を克服することも期待される。 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.
　かかる状況において、ＭＲＳＡに対するアミノグリコシド系抗生物質の活性増強作用を有する物質を提供することは、ＭＲＳＡ感染症やアミノグリコシド系抗生物質耐性を含む多剤耐性菌を起因とする感染症の新しい治療薬を提供するものであり大いに期待される。 Under such circumstances, 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.
　本発明者らは、微生物の生産する代謝産物を対象にアミノグリコシド系抗生物質であるアルベカシンのＭＲＳＡに対する耐性克服物質を探索した結果、新たに土壌から分離した糸状菌ＦＫＩ－４４２９株の培養液中にアルベカシン耐性克服作用を有する物質が産生されていることを見出した。次いで該培養物を精製、単離した結果、アルベカシン耐性克服作用を有するＦＫＩ－４４２９－１物質、ＦＫＩ－４４２９－２物質、ＦＫＩ－４４２９－３物質、およびＦＫＩ－４４２９－４物質の４種の化合物を得た。以下、これらを総称してＦＫＩ－４４２９物質と呼ぶ。すなわち、ＦＫＩ－４４２９物質とは、ＦＫＩ－４４２９－１物質、ＦＫＩ－４４２９－２物質、ＦＫＩ－４４２９－３物質、およびＦＫＩ－４４２９－４物質の少なくともいずれかひとつである。ＦＫＩ－４４２９物質のような化学構造を有する物質は従来全く知られていなかった。 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. That is, 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.
　本発明は、かかる知見に基づいて完成されたものであって、請求の範囲第１項に記載するように下記式［Ｉ］で表される新規ＦＫＩ－４４２９－１物質と、請求の範囲第２項に記載するように下記式［ＩＩ］で表される新規ＦＫＩ－４４２９－２物質と、請求の範囲第３項に記載するように下記式［ＩＩＩ］で表される新規ＦＫＩ－４４２９－３物質と、請求の範囲第４項に記載するように下記式［ＩＶ］で表される新規ＦＫＩ－４４２９－４物質とである。 The present invention has been completed based on such findings, and as described in claim 1, a novel FKI-4429-1 substance represented by the following formula [I], and A novel FKI-4429-2 substance represented by the following formula [II] as described in item 2 and a novel FKI-4429-2 represented by the following formula [III] as described in claim 3 3 substances and a novel FKI-4429-4 substance represented by the following formula [IV] as described in claim 4.
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　本発明はまた、請求の範囲第５項に記載するように、糸状菌に属し、式［Ｉ］で表されるＦＫＩ－４４２９－１物質と、式［ＩＩ］で表されるＦＫＩ－４４２９－２物質と、式［ＩＩＩ］で表されるＦＫＩ－４４２９－３物質と、式［ＩＶ］で表されるＦＫＩ－４４２９－４物質との少なくともいずれかひとつであるＦＫＩ－４４２９物質を生産する能力を有する微生物を、培地で培養し、培養物中に前記ＦＫＩ－４４２９物質を蓄積せしめる工程と、該培養物から前記ＦＫＩ－４４２９物質を採取する工程とを有することを特徴として構成されるＦＫＩ－４４２９物質の製造方法である。 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] A step of culturing a microorganism having a FKI-4429 substance in a culture medium, and a step of collecting the FKI-4429 substance from the culture. This is a method for producing 4429 substances.
　本発明はまた、請求の範囲第６項に記載するように、前記微生物が、ペニシリウム・エスピー（Ｐｅｎｉｃｉｌｌｉｕｍ　ｓｐ．）ＦＫＩ－４４２９（受託番号（国内寄託）　ＮＩＴＥ　Ｐ－８６９，受託番号（国際寄託）　ＮＩＴＥ　ＢＰ－８６９）である請求の範囲第５項に記載の製造方法である。 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).
　本発明は更に請求の範囲第７項に記載するように、ペニシリウム・エスピー（Ｐｅｎｉｃｉｌｌｉｕｍ　ｓｐ．）ＦＫＩ－４４２９（受託番号（国内寄託）　ＮＩＴＥ　Ｐ－８６９，受託番号（国際寄託）　ＮＩＴＥ　ＢＰ－８６９）株である。 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.
　さらにまた、請求の範囲第８項記載のように、本発明の抗菌剤は、式［Ｉ］で表されるＦＫＩ－４４２９－１物質と式［ＩＩ］で表されるＦＫＩ－４４２９－２物質と式［ＩＩＩ］で表されるＦＫＩ－４４２９－３物質と式［ＩＶ］で表されるＦＫＩ－４４２９－４物質との少なくともいずれかひとつと、アミノグリコシド系抗生物質とを備える。 Furthermore, as described in claim 8, 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.
　本発明の新規ＦＫＩ－４４２９－１物質と新規ＦＫＩ－４４２９－２物質と新規ＦＫＩ－４４２９－３物質と新規ＦＫＩ－４４２９－４物質とは、抗菌剤として利用されているアミノグリコシド系抗生物質と併用することにより、アミノグリコシド系抗生物質の活性を増強する。また、本発明の製造方法によれば、新規ＦＫＩ－４４２９－１物質と新規ＦＫＩ－４４２９－２物質と新規ＦＫＩ－４４２９－３物質と新規ＦＫＩ－４４２９－４物質とを製造することができる。 The 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.
本発明によるＦＫＩ－４４２９－１物質の紫外部吸収スペクトル（メタノール溶液中）を示したものである。2 shows an ultraviolet absorption spectrum (in a methanol solution) of the FKI-4429-1 substance according to the present invention. 本発明によるＦＫＩ－４４２９－１物質の赤外部吸収スペクトル（臭化カリウム法）を示したものである。2 shows an infrared absorption spectrum (potassium bromide method) of the FKI-4429-1 substance according to the present invention. 本発明によるＦＫＩ－４４２９－１物質のプロトン核磁気共鳴スペクトル（ＣＤ３ＯＨ中）を示したものである。2 shows a proton nuclear magnetic resonance spectrum (in CD 3 OH) of the FKI-4429-1 substance according to the present invention. 本発明によるＦＫＩ－４４２９－１物質のカーボン核磁気共鳴スペクトル（ＣＤ３ＯＨ中）を示したものである。2 shows a carbon nuclear magnetic resonance spectrum (in CD 3 OH) of the FKI-4429-1 substance according to the present invention. 本発明によるＦＫＩ－４４２９－２物質の紫外部吸収スペクトル（メタノール溶液中）を示したものである。2 shows an ultraviolet absorption spectrum (in a methanol solution) of the FKI-4429-2 substance according to the present invention. 本発明によるＦＫＩ－４４２９－２物質の赤外部吸収スペクトル（臭化カリウム法）を示したものである。FIG. 3 shows an infrared absorption spectrum (potassium bromide method) of FKI-4429-2 substance according to the present invention. FIG. 本発明によるＦＫＩ－４４２９－２物質のプロトン核磁気共鳴スペクトル（ＣＤ３ＯＨ中）を示したものである。2 shows a proton nuclear magnetic resonance spectrum (in CD 3 OH) of substance FKI-4429-2 according to the present invention. 本発明によるＦＫＩ－４４２９－２物質のカーボン核磁気共鳴スペクトル（ＣＤ３ＯＨ中）を示したものである。 3 shows a carbon nuclear magnetic resonance spectrum (in CD 3 OH) of the FKI-4429-2 substance according to the present invention. 本発明によるＦＫＩ－４４２９－３物質の紫外部吸収スペクトル（メタノール溶液中）を示したものである。2 shows an ultraviolet absorption spectrum (in a methanol solution) of the FKI-4429-3 substance according to the present invention. 本発明によるＦＫＩ－４４２９－３物質の赤外部吸収スペクトル（臭化カリウム法）を示したものである。FIG. 3 shows an infrared absorption spectrum (potassium bromide method) of FKI-4429-3 substance according to the present invention. FIG. 本発明によるＦＫＩ－４４２９－３物質のプロトン核磁気共鳴スペクトル（ＣＤ３ＯＤ中）を示したものである。FIG. 2 shows a proton nuclear magnetic resonance spectrum (in CD 3 OD) of FKI-4429-3 substance according to the present invention. FIG. 本発明によるＦＫＩ－４４２９－３物質のカーボン核磁気共鳴スペクトル（ＣＤ３ＯＤ中）を示したものである。2 shows a carbon nuclear magnetic resonance spectrum (in CD 3 OD) of the FKI-4429-3 substance according to the present invention. 本発明によるＦＫＩ－４４２９－４物質の紫外部吸収スペクトル（メタノール溶液中）を示したものである。2 shows an ultraviolet absorption spectrum (in a methanol solution) of the FKI-4429-4 substance according to the present invention. 本発明によるＦＫＩ－４４２９－４物質の赤外部吸収スペクトル（臭化カリウム法）を示したものである。FIG. 3 shows an infrared absorption spectrum (potassium bromide method) of FKI-4429-4 substance according to the present invention. FIG. 本発明によるＦＫＩ－４４２９－４物質のプロトン核磁気共鳴スペクトル（ＣＤ３ＯＤ中）を示したものである。2 shows a proton nuclear magnetic resonance spectrum (in CD 3 OD) of substance FKI-4429-4 according to the present invention. 本発明によるＦＫＩ－４４２９－４物質のカーボン核磁気共鳴スペクトル（ＣＤ３ＯＤ中）を示したものである。FIG. 2 shows a carbon nuclear magnetic resonance spectrum (in CD 3 OD) of FKI-4429-4 substance according to the present invention. FIG.
　本発明のＦＫＩ－４４２９物質は、糸状菌に属するＦＫＩ－４４２９物質を生産する能力を有する微生物を培養し、ＦＫＩ－４４２９物質を蓄積させた培養物から常法によって得ることができる。ＦＫＩ－４４２９物質は、前記式［Ｉ］、［ＩＩ］、［ＩＩＩ］、及び［ＩＶ］で表される。本発明に用いることのできる菌株としては、糸状菌に属するＦＫＩ－４４２９物質生産菌のすべてを使用することができる。その一例としては、本発明者等によって土壌より新たに分離されたペニシリウム・エスピー（Ｐｅｎｉｃｉｌｌｉｕｍ　ｓｐ．）ＦＫＩ－４４２９株を挙げることができる。 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]. As strains that can be used in the present invention, all FKI-4429 substance-producing bacteria belonging to filamentous fungi can be used. As an example, Penicillium sp. FKI-4429 strain newly isolated from soil by the present inventors can be mentioned.
　［ペニシリウム・エスピー（Ｐｅｎｉｃｉｌｌｉｕｍ　ｓｐ．）ＦＫＩ－４４２９株の菌学的性質］
１．形態的特徴
　本菌株は、ツァペック・イーストエキス寒天培地、麦芽汁寒天培地、２５％グリセリン・硝酸塩寒天培地で良好に生育し、各種寒天培地で分生子の着生は良好であった。 [Mycological properties of Penicillium sp. Strain FKI-4429]
1. Morphological characteristics The strain grew well on the Czapek yeast extract agar medium, the wort agar medium, and the 25% glycerin / nitrate agar medium, and the conidia was well established on the various agar mediums.
　麦芽汁寒天培地に生育したコロニーを顕微鏡で観察すると、菌糸は無色で隔壁を有している。分生子柄（５０～１２５×１．５～２．５μｍ）は、気菌糸より直立して生じ、分岐することはなかった。分生子柄の先端にはペニシルスが形成される。ペニシルスは二輪生で、３～５本のフィアライドが群生して構成される。フィアライドは円筒型で、大きさ１０．０～１２．５×２．３～２．７μｍであった。フィアライドの先端からフィアロ型分生子が形成され、培養時間の経過とともに連鎖状となる。分生子は紡錘型、緑色、大きさ２．５～５．０×２．３～２．７μｍで、表面は粗面であった。 When the colonies grown on the wort agar medium are observed with a microscope, the mycelium is colorless and has partition walls. The conidial pattern (50-125 × 1.5-2.5 μm) 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 μm. 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 μm in size, and the surface was rough.
　２．培養性状
各種寒天培地上で、２５℃、７日間培養した場合の肉眼的観察結果を表１に示す。 2. Table 1 shows the results of macroscopic observation when cultured on various agar media at 25 ° C for 7 days.
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
　３．生理的性状
　（１）最適生育条件
　　　本菌株の最適生育条件は、ｐＨ３～７、温度２６．１～３６．９℃である。
　２）生育の範囲
　　　本菌株の生育範囲は、ｐＨ２～９、温度１０．２～３８．６℃である。
　３）好気性、嫌気性の区別
　　　好気性。 3. Physiological properties (1) 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.
[規則91に基づく訂正 01.06.2011]　
　上記ＦＫＩ－４４２９株の形態的特徴、培養性状および生理的性状に基づき、既知菌種との比較を試みた。この結果、本菌株はペニシリウム（Ｐｅｎｉｃｉｌｌｉｕｍ）に属する一菌株と同定し、ペニシリウム・エスピーＦＫＩ－４４２９と命名した。なお本菌株はペニシリウム・エスピーＦＫＩ－４４２９（Ｐｅｎｉｃｉｌｌｉｕｍ　ｓｐ．ＦＫＩ－４４２９）として、日本国千葉県木更津市かずさ鎌足２－５－８（郵便番号２９２－０８１８）に所在する独立行政法人製品評価技術基盤機構特許微生物寄託センターに、平成２２年１月２２日に寄託されている。受託番号（国内寄託）はＮＩＴＥ　Ｐ－８６９である。また、本菌株は、特許手続上の微生物の寄託の国際的承認に関するブタペスト条約に基づき、日本国千葉県木更津市かずさ鎌足２－５－８（郵便番号２９２－０８１８）に所在する独立行政法人製品評価技術基盤機構特許微生物寄託センターに、平成２３年１月１７日に、国際寄託へ移管されている。受託番号（国際寄託）はＮＩＴＥ　ＢＰ－８６９である。 [Correction based on Rule 91 01.06.2011]
Based on the morphological characteristics, culture properties, and physiological properties of the FKI-4429 strain, an attempt was made to compare with known bacterial species. As a result, this strain was identified as a strain belonging to Penicillium and named Penicillium sp. FKI-4429. This strain is Penicillium sp. FKI-4429 (Penicillium sp. FKI-4429), an independent administrative agency product evaluation technology located in 2-5-8 Kazusa Kamashi, Kisarazu City, Chiba Prefecture, Japan (zip code 292-0818). Deposited on January 22, 2010 at the Foundation Organization for Microbial Deposits. The accession number (domestic deposit) is NITE P-869. 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.
　［培養方法］
　ＦＫＩ－４４２９物質は糸状菌に属し、ＦＫＩ－４４２９物質生産能を有する微生物を培養することによって得られる。培養は一般微生物の培養方法に準じて行われる。 [Culture method]
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.
　ＦＫＩ－４４２９物質生産に適した栄養源としては、糸状菌の栄養源として使用し得るものであればよい。例えば、市販のペプトン、肉エキス、コーン・スティープ・リカー、綿実粉、落花生粉、大豆粉、酵母エキス、ＮＺ－アミン、カゼインの水和物、硝酸ソーダ、硝酸アンモニウム、硫酸アンモニウム等の窒素源、グリセリン、澱粉、グルコース、ガラクトース、マンノース等の炭水化物、あるいは脂肪等の炭素源、及び食塩、リン酸塩、炭酸カルシウム、硫酸マグネシウム等の無機塩を単独であるいは組み合わせて使用することができる。 As a nutrient source suitable for FKI-4429 substance production, any nutrient source that can be used as a nutrient source for filamentous fungi may be used. 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 Further, 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.
　その他必要に応じて微量の金属塩、消泡剤として動・植・鉱物油等を添加することもできる。これらのものは生産菌が利用しＦＫＩ－４４２９物質の生産の役だつものであればよく、公知の糸状菌の培養材料はすべて用いることができる。ＦＫＩ－４４２９物質の大量培養には液体培養が好ましく、培養温度は生産菌が発育し、ＦＫＩ－４４２９物質を生産できる範囲で適用することができる。培養は以上に述べた条件を使用するＦＫＩ－４４２９物質生産菌の性質に応じて適宜選択して行なうことができる。 Other trace amounts of 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.
　［精製方法］
　ＦＫＩ－４４２９物質は、培養液よりクロロホルム、酢酸エチル等の水不混和性の有機溶媒で抽出することができる。上述の抽出法に加え、脂溶性物質の採取に用いられる公知の方法、例えば吸着クロマトグラフィー、ゲル濾過クロマトグラフィー、薄層クロマトグラフィーよりのかき取り、遠心向流分配クロマトグラフィー、高速液体クロマトグラフィー等を適宜組み合わせることによってあるいは繰り返すことによって純粋に採取することができる。 [Purification method]
The FKI-4429 substance can be extracted from the culture solution with a water-immiscible organic solvent such as chloroform or ethyl acetate. In addition to the extraction methods described above, 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.
　［理化学的性状］
　次に、本発明のＦＫＩ－４４２９物質の理化学的性状について説明する。 [Physical and chemical properties]
Next, the physicochemical properties of the FKI-4429 substance of the present invention will be described.
　１．ＦＫＩ－４４２９－１物質
　（１）性状：白色粉末
　（２）分子式：Ｃ１９Ｈ３０Ｏ５
　　　　　　　ＨＲ－ＥＳＩ－ＭＳ（ｍ／ｚ）［Ｍ＋Ｎａ］＋　計算値３６１．１９９１，　実測値３６１．２００１
　（３）分子量：３３８
　　　　　　　ＥＳＩ－ＭＳ（ｍ／ｚ）で［Ｍ＋Ｎａ］＋３６１を観測
　（４）紫外部吸収スペクトル（ＵＶスペクトル）：メタノール（ＣＨ３ＯＨ）溶液中で測定した紫外部吸収スペクトルは図１に示すとおりであり、λｍａｘ（ε）：２１５ｎｍ（２０５００）の吸収極大を示す。
　（５）赤外部吸収スペクトル（ＩＲスペクトル）：臭化カリウム（ＫＢｒ）錠剤法で測定した赤外吸収スペクトルは図２に示すとおりであり、νｍａｘは、３４３５，２９５６，２９２５，２８５７，１７４３，１６４１，１４４６ｃｍ－１等に特徴的な吸収極大を示す。
　（６）溶剤に対する溶解性：メタノール、酢酸エチルおよびクロロホルムに可溶。水、ヘキサンに不溶。
　（７）プロトン及びカーボン核磁気共鳴スペクトル（１Ｈ－ＮＭＲスペクトル及び１３Ｃ－ＮＭＲスペクトル）：ＣＤ３ＯＨ中で、バリアン社４００及び１００ＭＨｚ核磁気共鳴スペクトロメータで測定した水素の化学シフト（ｐｐｍ）及び炭素の化学シフト（ｐｐｍ）は下記に示すとおりである。なお（　）内は水素の数を示す。
　δＨ：０．９０（３Ｈ），０．９６（３Ｈ），１．１８～１．３７（１０Ｈ），１．６８（３Ｈ），２．４５（１Ｈ），２．４８（１Ｈ），２．７３（１Ｈ），３．１７（１Ｈ），３．２３（１Ｈ），４．０５（１Ｈ），４．５８（１Ｈ），５．１８（１Ｈ），７．１８（１Ｈ）
　δＣ：１２．５，１４．３，２１．１，２３．６，２８．５，３０．４，３１．１，３２．９，３３．２，３５．１，３８．４，６４．６，８８．７，１２６．７，１３０．３，１３７．５，１４０．８，１６７．９，１７４．１ 1. FKI-4429-1 substance (1) Property: white powder (2) Molecular formula: C 19 H 30 O 5
HR-ESI-MS (m / z) [M + Na] + calculated value 361.1991, actually measured value 361.2001
(3) Molecular weight: 338
Observation of [M + Na] + 361 by ESI-MS (m / z) (4) UV absorption spectrum (UV spectrum): UV absorption spectrum measured in methanol (CH 3 OH) solution is as shown in FIG. Yes, λ max (ε): 215 nm (20500) absorption maximum.
(5) Infrared absorption spectrum (IR spectrum): The infrared absorption spectrum measured by the potassium bromide (KBr) tablet method is as shown in FIG. 2, and ν max is 3435, 2956, 2925, 2857, 1743, A characteristic absorption maximum is shown at 1641, 1446 cm −1 and the like.
(6) Solubility in solvents: soluble in methanol, ethyl acetate and chloroform. Insoluble in water and hexane.
(7) 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.
δ H : 0.90 (3H), 0.96 (3H), 1.18 to 1.37 (10H), 1.68 (3H), 2.45 (1H), 2.48 (1H), 2 .73 (1H), 3.17 (1H), 3.23 (1H), 4.05 (1H), 4.58 (1H), 5.18 (1H), 7.18 (1H)
δ C: 12.5,14.3,21.1,23.6,28.5,30.4,31.1,32.9,33.2,35.1,38.4,64.6 , 88.7, 126.7, 130.3, 137.5, 140.8, 167.9, 174.1
　以上のように、ＦＫＩ－４４２９－１物質の各種理化学性状やスペクトルデータを詳細に検討した。その結果、ＦＫＩ－４４２９－１物質は下記の式［Ｉ］で表される化学構造であることが決定された。 As described above, various physicochemical properties and spectrum data of the FKI-4429-1 substance were examined in detail. As a result, FKI-4429-1 substance was determined to have a chemical structure represented by the following formula [I].
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　２．ＦＫＩ－４４２９－２物質
　（１）性状：白色粉末
　（２）分子式：Ｃ１９Ｈ３０Ｏ５
　　　　　　　ＨＲ－ＥＳＩ－ＭＳ（ｍ／ｚ）［Ｍ＋Ｎａ］＋　計算値３６１．１９９１，実測値３６１．１９８５
　（３）分子量：３３８
　　　　　　　ＥＳＩ－ＭＳ（ｍ／ｚ）で［Ｍ＋Ｎａ］＋３６１を観測
　（４）紫外部吸収スペクトル：メタノール溶液中で測定した紫外部吸収スペクトルは図５に示すとおりであり、λｍａｘ（ε）：２１４ｎｍ（２５２００）の吸収極大を示す。
　（５）赤外部吸収スペクトル：臭化カリウム錠剤法で測定した赤外吸収スペクトルは図６に示すとおりであり、νｍａｘは、３４４４，２９５６，２９２５，２８５８，１７５１，１６８５，１６３３，１４４６ｃｍ－１等に特徴的な吸収極大を示す。
　（６）溶剤に対する溶解性：メタノール、酢酸エチルおよびクロロホルムに可溶。水、ヘキサンに不溶。
　（７）プロトン及びカーボン核磁気共鳴スペクトル：ＣＤ３ＯＨ中で、バリアン社４００及び１００ＭＨｚ核磁気共鳴スペクトロメータで測定した水素の化学シフト（ｐｐｍ）及び炭素の化学シフト（ｐｐｍ）は下記に示すとおりである。なお（　）内は水素の数を示す。
　δＨ：０．９１（３Ｈ），０．９５（３Ｈ），１．１８～１．３７（１０Ｈ），１．６６（３Ｈ），２．４３（１Ｈ），２．８０（２Ｈ），３．２０（２Ｈ），４．１６（１Ｈ），４．７１（１Ｈ），５．３４（１Ｈ），６．８０（１Ｈ）
　δＣ：１３．７，１４．３，２１．２，２３．６，２３．６，２８．６，３０．６，３３．０，３３．１，３８．７，４８．０，７７．１，７９．８，１３０．４，１３２．５，１３３．４，１３５．３，１７０．０，１７２．７ 2. 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 λ max (ε): 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. 6, and ν max is 3444, 2956, 2925, 2858, 1751, 1685, 1633, 1446 cm −1. The characteristic absorption maximum is shown.
(6) Solubility in solvents: soluble in methanol, ethyl acetate and chloroform. Insoluble in water and hexane.
(7) 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.
δ H : 0.91 (3H), 0.95 (3H), 1.18 to 1.37 (10H), 1.66 (3H), 2.43 (1H), 2.80 (2H), 3 .20 (2H), 4.16 (1H), 4.71 (1H), 5.34 (1H), 6.80 (1H)
δ C : 13.7, 14.3, 21.2, 23.6, 23.6, 28.6, 30.6, 33.0, 33.1, 38.7, 48.0, 77.1 79.8, 130.4, 132.5, 133.4, 135.3, 170.0, 172.7.
　以上のように、ＦＫＩ－４４２９－２物質の各種理化学性状やスペクトルデータを詳細に検討した。その結果、ＦＫＩ－４４２９－２物質は下記の式［ＩＩ］で表される化学構造であることが決定された。 As described above, various physicochemical properties and spectrum data of the FKI-4429-2 substance were examined in detail. As a result, FKI-4429-2 substance was determined to have a chemical structure represented by the following formula [II].
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　３．ＦＫＩ－４４２９－３物質
　（１）性状：白色粉末
　（２）分子式：Ｃ１９Ｈ２８Ｏ５
　　　　　　　ＨＲ－ＥＳＩ－ＭＳ（ｍ／ｚ）［Ｍ＋Ｎａ］＋　計算値３５９．１８３４，実測値３５９．１８４９
　（３）分子量：３３６
　　　　　　　ＥＳＩ－ＭＳ（ｍ／ｚ）で［Ｍ＋Ｎａ］＋３５９を観測
　（４）紫外部吸収スペクトル：メタノール溶液中で測定した紫外部吸収スペクトルは図９に示すとおりであり、λｍａｘ（ε）：２０６ｎｍ（６７０００），２５１ｎｍ（６１７０）の吸収極大を示す。
　（５）赤外部吸収スペクトル：臭化カリウム錠剤法で測定した赤外吸収スペクトルは図１０に示すとおりであり、νｍａｘは、３４２９，２９５６，２９２５，２８５８，１７５８，１７０５，１６４７ｃｍ－１等に特徴的な吸収極大を示す。
　（６）溶剤に対する溶解性：メタノール、酢酸エチルおよびクロロホルムに可溶。水、ヘキサンに不溶。
　（７）プロトン及びカーボン核磁気共鳴スペクトル：ＣＤ３ＯＤ中で、バリアン社４００及び１００ＭＨｚ核磁気共鳴スペクトロメータで測定した水素の化学シフト（ｐｐｍ）及び炭素の化学シフト（ｐｐｍ）は下記に示すとおりである。なお（　）内は水素の数を示す。
　δＨ：０．９０（３Ｈ），０．９４（３Ｈ），１．２０～１．４０（１０Ｈ），１．７１（３Ｈ），２．４４（１Ｈ），４．１９（１Ｈ），５．１７（１Ｈ），５．３０（１Ｈ），６．９０（１Ｈ），７．３６（１Ｈ），７．７８（１Ｈ）
　δＣ：１３．９，１５．０，２１．６，２４．１，２９．０，３０．０，３３．３，３３．５，３８．８，７７．０，８４．２，１２５．２，１２８．１，１３１．４，１３２．３，１３５．５，１５４．８，１７１．０，１７２．０ 3. Substance FKI-4429-3 (1) Property: white powder (2) Molecular formula: C 19 H 28 O 5
HR-ESI-MS (m / z) [M + Na] + calculated value 359.1834, actual value 359.1849
(3) Molecular weight: 336
Observation of [M + Na] + 359 by ESI-MS (m / z) (4) Ultraviolet absorption spectrum: the ultraviolet absorption spectrum measured in a methanol solution is as shown in FIG. 9, and λ max (ε): 206 nm The absorption maximum is (67000), 251 nm (6170).
(5) Infrared absorption spectrum: The infrared absorption spectrum measured by the potassium bromide tablet method is as shown in FIG. 10, and ν max is 3429, 2956, 2925, 2858, 1758, 1705, 1647 cm −1 and the like. It shows a characteristic absorption maximum.
(6) Solubility in solvents: Soluble in methanol, ethyl acetate and chloroform. Insoluble in water and hexane.
(7) 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.
δ H : 0.90 (3H), 0.94 (3H), 1.20 to 1.40 (10H), 1.71 (3H), 2.44 (1H), 4.19 (1H), 5 .17 (1H), 5.30 (1H), 6.90 (1H), 7.36 (1H), 7.78 (1H)
δ C : 13.9, 15.0, 21.6, 24.1, 29.0, 30.0, 33.3, 33.5, 38.8, 77.0, 84.2, 125.2 , 128.1, 131.4, 132.3, 135.5, 154.8, 171.0, 172.0
　以上のように、ＦＫＩ－４４２９－３物質の各種理化学性状やスペクトルデータを詳細に検討した。その結果、ＦＫＩ－４４２９－３物質は下記の式［ＩＩＩ］で表される化学構造であることが決定された。 As described above, various physicochemical properties and spectrum data of the FKI-4429-3 substance were examined in detail. As a result, the substance FKI-4429-3 was determined to have a chemical structure represented by the following formula [III].
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　４．ＦＫＩ－４４２９－４物質
　（１）性状：白色粉末
　（２）分子式：Ｃ１９Ｈ２８Ｏ５
　　　　　　　ＨＲ－ＦＡＢ－ＭＳ（ｍ／ｚ）［Ｍ＋Ｈ］＋　計算値３３７．１９５６，　実測値３３７．１９８６
　（３）分子量：３３６
　　　　　　　ＦＡＢ－ＭＳ（ｍ／ｚ）で［Ｍ＋Ｈ］＋３３７を観測
　（４）紫外部吸収スペクトル：メタノール溶液中で測定した紫外部吸収スペクトルは図１３に示すとおりであり、λｍａｘ（ε）：２０２ｎｍ（６７０００），２５８ｎｍ（６９８０）の吸収極大を示す。
　（５）赤外部吸収スペクトル：臭化カリウム錠剤法で測定した赤外吸収スペクトルは図１４に示すとおりであり、νｍａｘは、３４５２，２９５６，２９２５，２８５７，１７０３，１６３９，１４５７，１３８０ｃｍ－１等に特徴的な吸収極大を示す。
　（６）溶剤に対する溶解性：メタノール、酢酸エチルおよびクロロホルムに可溶。水、ヘキサンに不溶。
　（７）プロトン及びカーボン核磁気共鳴スペクトル：ＣＤ３ＯＤ中で、バリアン社４００及び１００ＭＨｚ核磁気共鳴スペクトロメータで測定した水素の化学シフト（ｐｐｍ）及び炭素の化学シフト（ｐｐｍ）は下記に示すとおりである。なお（　）内は水素の数を示す。
　δＨ：０．８０（３Ｈ），０．８８（３Ｈ），１．１０～１．２５（１０Ｈ），１．６５（３Ｈ），２．３８（１Ｈ），４．４５（１Ｈ），４．５２（１Ｈ），５．２５（１Ｈ），６．５５（１Ｈ），７．１０（１Ｈ），７．１８（１Ｈ）
　δＣ：１０．９，１３．３，１９．９，２２．５，２７．０，２９．０，３２．０，３２．３，３７．３，６３．８，８８．２，１２３．８，１２６．０，１２８．０，１３８．０，１４０．０，１５１．０，１６３．０，１６９．８ 4). 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 λ max (ε): 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. 14, and ν max is 3452, 2956, 2925, 2857, 1703, 1639, 1457, 1380 cm −1. The characteristic absorption maximum is shown.
(6) Solubility in solvents: soluble in methanol, ethyl acetate and chloroform. Insoluble in water and hexane.
(7) 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.
δ H : 0.80 (3H), 0.88 (3H), 1.10 to 1.25 (10H), 1.65 (3H), 2.38 (1H), 4.45 (1H), 4 .52 (1H), 5.25 (1H), 6.55 (1H), 7.10 (1H), 7.18 (1H)
δ C: 10.9,13.3,19.9,22.5,27.0,29.0,32.0,32.3,37.3,63.8,88.2,123.8 , 126.0, 128.0, 138.0, 140.0, 151.0, 163.0, 169.8
　以上のように、ＦＫＩ－４４２９－４物質の各種理化学性状やスペクトルデータを詳細に検討した。その結果、ＦＫＩ－４４２９－４物質は下記の式［ＩＶ］で表される化学構造であることが決定された。 As described above, various physicochemical properties and spectrum data of FKI-4429-4 substance were examined in detail. As a result, the substance FKI-4429-4 was determined to have a chemical structure represented by the following formula [IV].
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　以下に本発明の実施例を挙げて本発明を具体的に説明するが、本発明はこれのみに限定されるものではない。 Hereinafter, the present invention will be specifically described with reference to examples of the present invention, but the present invention is not limited to these examples.
　［培養方法］
　寒天斜面培地で培養したＦＫＩ－４４２９株を、種培地１０ｍＬを分注した大試験管１本に１白金耳接種し、２７℃で３日間シェイカー（３００ｒｐｍ）で培養した。寒天斜面培地は、グリセロール０．１％（和光純薬）、リン酸二水素カリウム０．０８％（関東化学）、リン酸水素二カリウム０．０２％（関東化学）、硫酸マグネシウム七水和物０．０２％（和光純薬）、塩化カリウム０．０２％（関東化学）、硝酸ナトリウム０．２％（和光純薬）、酵母エキス０．０２％（オリエンタル酵母）、寒天１．５％（清水食品）を含み、ｐＨ６．０に調製したものである。種培地は、グルコース２．０％（和光純薬）、酵母エキス０．２％（オリエンタル酵母）、硫酸マグネシウム七水和物０．０５％（和光純薬）ポリペプトン０．５％（和光純薬）、リン酸二水素カリウム０．１％（関東化学）、寒天０．１％（清水食品）を含み、ｐＨ６．０に調製したものである。その後、生産培地１００ｍＬを入れた５００ｍＬ容三角フラスコ４本に１％ずつ植菌し、２７℃、２１０ｒｐｍで６日間、ロータリーシェーカーで培養した。生産培地は、水溶性でんぷん３．０％（ホクレン）、グリセロール１．０％（和光純薬）、ソイビーンミール２．０％（東京保存食料）、ドライイースト０．３％（オリエンタル酵母）、塩化カリウム０．３％（関東化学）、硫酸マグネシウム七水和物０．０５％（和光純薬）、炭酸カルシウム０．２％（関東化学）、リン酸水素二カリウム０．０５％（関東化学）を含み、ｐＨ７．０に調製したものである。 [Culture method]
One platinum loop of the FKI-4429 strain cultured on an agar slant medium was inoculated into one large test tube into which 10 mL of the seed medium was dispensed, and cultured at 27 ° C. for 3 days with a shaker (300 rpm). 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.
　［精製方法］
　培養終了後、この培養液（４００ｍＬ）にエタノール（４００ｍＬ）を加え、３０分撹拌後遠心してエタノール抽出液を得た。エタノール抽出液から減圧下でエタノールを留去して得られた水溶液より、酸性条件下、酢酸エチル（４００ｍＬ）で三度抽出した。酢酸エチル層を濃縮乾固して得た活性粗物質（１９２ｍｇ）をシリカゲルカラム（シリカゲル６０（メッシュ６０－２３０）、メルク社、２０φ×７０ｍｍ）にて粗精製を行った。クロロホルムでシリカゲルカラムを洗浄した。こののち、クロロホルム－メタノール（１００：０、１００：１、５０：１、１０：１、１：１、０：１００）の各混合溶媒を展開溶媒とするクロマトグラフィーを行い、溶出液を溶出条件毎に分画した。活性画分（１０：１）を濃縮乾固することで、褐色油状物質３６ｍｇを得た。 [Purification method]
After completion of the culture, ethanol (400 mL) was added to the culture solution (400 mL), stirred for 30 minutes and then centrifuged to obtain an ethanol extract. From the aqueous solution obtained by distilling off ethanol from the ethanol extract under reduced pressure, extraction was performed three times with ethyl acetate (400 mL) under acidic conditions. The active crude material (192 mg) obtained by concentrating and drying the ethyl acetate layer was roughly purified on a silica gel column (silica gel 60 (mesh 60-230), Merck, 20φ × 70 mm). The silica gel column was washed with chloroform. After that, chromatography using chloroform-methanol (100: 0, 100: 1, 50: 1, 10: 1, 1: 1, 0: 100) as a developing solvent is performed, and the eluate is subjected to elution conditions. It fractionated every time. The active fraction (10: 1) was concentrated to dryness to obtain 36 mg of a brown oily substance.
　続いて、活性画分（１０：１）３６ｍｇを少量のメタノールに溶解し、分取ＨＰＬＣ（カラム：ＸＢｒｉｄｇｅ　Ｃ１８、１０φ×２５０ｍｍ、センシュー科学）により精製を行った。５０％アセトニトリル水溶液／０．１％トリフルオロ酢酸を移動相とし、４ｍＬ／ｍｉｎの流速において、ＵＶ２１０ｎｍの吸収をモニターした。保持時間１９ｍｉｎ、２６ｍｉｎ、３２ｍｉｎ、３４ｍｉｎに活性を示すピークを観察し、これらのピークを分取した。分取液を減圧下で濃縮乾固することにより、ＦＫＩ－４４２９－１物質、ＦＫＩ－４４２９－２物質、ＦＫＩ－４４２９－３物質、ＦＫＩ－４４２９－４物質をそれぞれ収量０．７１ｍｇ、２．３４ｍｇ、１．１７ｍｇ、２．５７ｍｇで単離した。 Subsequently, 36 mg of the active fraction (10: 1) was dissolved in a small amount of methanol and purified by preparative HPLC (column: X Bridge C18, 10φ × 250 mm, Senshu Science). Absorption at UV 210 nm was monitored using a 50% acetonitrile aqueous solution / 0.1% trifluoroacetic acid as a mobile phase at a flow rate of 4 mL / min. Peaks showing activity were observed at retention times of 19 min, 26 min, 32 min, and 34 min, and these peaks were collected. The aliquot was concentrated to dryness under reduced pressure to yield 0.71 mg, FKI-4429-1, Substance FKI-4429-2, FKI-4429-3, and FKI-4429-4, respectively. Isolated at 34 mg, 1.17 mg, 2.57 mg.
　［ペーパーディスク法によるアルベカシン耐性克服作用の評価］
　試験菌として、臨床分離されたメチシリン耐性Ｓｔａｐｈｙｌｏｃｏｃｃｕｓ　ａｕｒｅｕｓ（ＭＲＳＡ）ＴＨ－１４６６株を用いた。Ｓ．ａｕｒｅｕｓ　ＴＨ－１４６６株は、Ｍｕｅｌｌｅｒ－Ｈｉｎｔｏｎ　ｂｒｏｔｈ（２．１％ｗ／ｖ、Ｄｉｆｃｏ社）にて３５℃、２０時間培養した。この後、ＭＨＡ培地（Ｍｕｅｌｌｅｒ－Ｈｉｎｔｏｎ　ｂｒｏｔｈ　２．１％ｗ／ｖ、Ａｇａｒ１．５％）および同組成の培地にアルベカシン（明治製菓株式会社：硫酸アルベカシン、力価７１０ｍｇ／ｍＬ）を試験菌の生育に影響を与えない濃度、すなわち最終濃度８μｇ／ｍＬとなるように添加した培地に１％植菌した。 [Evaluation of arbekacin resistance overcoming effect by paper disc method]
As a test bacterium, clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) TH-1466 strain was used. S. The aureus TH-1466 strain was cultured at 35 ° C. for 20 hours in Mueller-Hinton broth (2.1% w / v, Difco). Thereafter, Arbekacin (Meiji Seika Co., Ltd .: Arbekacin sulfate, titer 710 mg / mL) was grown on the MHA medium (Mueller-Hinton broth 2.1% w / v, Agar 1.5%) and the medium having the same composition. 1% was inoculated into the medium added so that the final concentration would be 8 μg / mL.
　試験菌に対する各培地上での抗菌活性は、ペーパーディスク法（直径６ｍｍ、薄手：Ａｄｖａｎｔｅｃ社）にて、３５℃で２０時間培養した後の阻止円径の直径を測定した。測定した阻止円径を単位ｍｍで表記し、表２に示した。その結果、ＦＫＩ－４４２９－１、２、３および４の各物質はそれぞれ３０、１０、３および０．３μｇ／ディスク条件下において、アルベカシン非存在下では阻止円が観察されなかった。これに対して、アルベカシン存在下ではいずれも８ｍｍから１３ｍｍの直径の阻止円が観察され、アルベカシン活性増強作用が確認された。表２において「ＮＴ」とは、試験を行わなかったことを示す。 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. As a result, no inhibition circle was observed for FKI-4429-1, 2, 3 and 4 under the conditions of 30, 10, 3 and 0.3 μg / disk, respectively, in the absence of arbekacin. On the other hand, in the presence of arbekacin, a blocking circle having a diameter of 8 mm to 13 mm was observed in all, confirming the arbekacin activity enhancing action. In Table 2, “NT” indicates that the test was not performed.
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
　［微量液体希釈法によるアルベカシン耐性克服作用の評価］
　ＦＫＩ－４４２９物質に関して、微量液体希釈法に従い、ＭＲＳＡ　ＴＨ－１４６６株に対するアルベカシン耐性克服活性を評価した。評価は、日本化学療法学会標準法（Ｃｈｅｍｏｔｈｅｒａｐｙ　３８巻、１０３－１０５頁、１９９０年）を一部改変して行った。９６　ｗｅｌｌ　ｐｌａｔｅ（Ｃｏｒｎｉｎｇ社、米国）の各ｗｅｌｌに、Ｍｕｅｌｌｅｒ－Ｈｉｎｔｏｎ　ｂｒｏｔｈ（２．１％ｗ／ｖ）を８５μＬ添加した後、あらかじめ滅菌水で段階希釈しておいたアルベカシンを最終濃度４．８×１０－４から２５６μｇ／ｍＬとなるように各ｗｅｌｌに５μＬ添加した。 [Evaluation of arbekacin resistance overcoming effect by micro liquid dilution method]
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 μL 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 μL was added to each well so as to be from × 10 −4 to 256 μg / mL.
　さらに、これら各ｗｅｌｌにＦＫＩ－４４２９－１，－２、および－４の各物質のメタノール溶液をそれぞれそれ自身では生育に影響を与えない最終濃度６４，１２８および１６μｇ／ｍＬとなるように５μＬ添加した。よく混合した後、ＭＲＳＡ　ＴＨ－１４６６株を０．５　ＭｃＦａｒｌａｎｄ（約１０８　ＣＦＵ／ｍＬ）相当に懸濁し、これを同培地で１０倍に希釈した接種菌液を各ｗｅｌｌに５μＬ接種した。３５℃、２０時間培養後、菌の発育が肉眼的に認められないｗｅｌｌのうち、最小のアルベカシンの濃度をもって最小発育阻止濃度（ＭＩＣ）とした。 Furthermore, 5 μL of a methanol solution of each substance of FKI-4429-1, -2, and -4 is added to each of these wells so that the final concentrations of 64, 128, and 16 μg / mL do not affect the growth. did. After mixing well, the MRSA TH-1466 strain was suspended in an amount equivalent to 0.5 McFarland (about 10 8 CFU / mL), and 5 μL of each well was inoculated with an inoculum solution diluted 10-fold with the same medium. Among wells in which the growth of bacteria was not visually observed after culturing at 35 ° C. for 20 hours, the minimum concentration of arbekacin was defined as the minimum inhibitory concentration (MIC).
　アルベカシンとＦＫＩ－４４２９物質併用時のＭＩＣは表３に示した。アルベカシン単独時ではＭＩＣが１２８μｇ／ｍＬであったが、ＦＫＩ－４４２９物質の併用によりＭＩＣは最大で４μｇ／ｍＬまで低下し、最大３２倍の活性増強が確認された。 Table 3 shows the MICs when arbekacin and FKI-4429 were used in combination. When arbekacin alone was used, the MIC was 128 μg / mL, but when the FKI-4429 substance was used in combination, the MIC decreased to a maximum of 4 μg / mL, confirming a 32-fold increase in activity.
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
　以上のとおり、新規ＦＫＩ－４４２９物質を生産する能力を有するペニシリウム属に属するＦＫＩ－４４２９株を代表とする微生物を培地に培養して、その培養液中から採取したＦＫＩ－４４２９物質は、抗菌剤として利用されているアミノグリコシド系抗生物質と併用することによりその効果を増強する作用を有することから、メチシリン耐性黄色ブドウ球菌（ＭＲＳＡ）感染症やアミノグリコシド系抗生物質耐性を含む多剤耐性菌を起因とする感染症の治療薬として有用であると期待される。 As described above, 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.

Claims (8)

  1. 　下記式［Ｉ］で表されるＦＫＩ－４４２９－１物質。
    Figure JPOXMLDOC01-appb-C000001
         A FKI-4429-1 substance represented by the following formula [I].
    Figure JPOXMLDOC01-appb-C000001
  2. 　下記式［ＩＩ］で表されるＦＫＩ－４４２９－２物質。
    Figure JPOXMLDOC01-appb-C000002
         FKI-4429-2 substance represented by the following formula [II].
    Figure JPOXMLDOC01-appb-C000002
  3. 　下記式［ＩＩＩ］で表されるＦＫＩ－４４２９－３物質。
    Figure JPOXMLDOC01-appb-C000003
         FKI-4429-3 substance represented by the following formula [III].
    Figure JPOXMLDOC01-appb-C000003
  4. 　下記式［ＩＶ］で表されるＦＫＩ－４４２９－４物質。
    Figure JPOXMLDOC01-appb-C000004
         FKI-4429-4 substance represented by the following formula [IV].
    Figure JPOXMLDOC01-appb-C000004
  5. 　糸状菌に属し、下記式［Ｉ］で表されるＦＫＩ－４４２９－１物質と、下記式［ＩＩ］で表されるＦＫＩ－４４２９－２物質と、下記式［ＩＩＩ］で表されるＦＫＩ－４４２９－３物質と、下記式［ＩＶ］で表されるＦＫＩ－４４２９－４物質との少なくともいずれかひとつであるＦＫＩ－４４２９物質を生産する能力を有する微生物を、培地で培養し、培養物中に前記ＦＫＩ－４４２９物質を蓄積せしめる工程と、該培養物から前記ＦＫＩ－４４２９物質を採取する工程とを有することを特徴とするＦＫＩ－４４２９物質の製造方法。
    Figure JPOXMLDOC01-appb-C000005
    Figure JPOXMLDOC01-appb-C000006
    Figure JPOXMLDOC01-appb-C000007
    Figure JPOXMLDOC01-appb-C000008
         An FKI-4429-1 substance represented by the following formula [I], an FKI-4429-2 substance represented by the following formula [II], and an FKI- represented by the following formula [III] A microorganism having the ability to produce the FKI-4429 substance, which is at least one of the 4429-3 substance and the FKI-4429-4 substance represented by the following formula [IV], is cultured in a medium, A method of accumulating the FKI-4429 substance in the method, and a step of collecting the FKI-4429 substance from the culture.
    Figure JPOXMLDOC01-appb-C000005
    Figure JPOXMLDOC01-appb-C000006
    Figure JPOXMLDOC01-appb-C000007
    Figure JPOXMLDOC01-appb-C000008
  6. 　前記微生物が、ペニシリウム・エスピー（Ｐｅｎｉｃｉｌｌｉｕｍ　ｓｐ．）ＦＫＩ－４４２９（受託番号（国内寄託）　ＮＩＴＥ　Ｐ－８６９，受託番号（国際寄託）　ＮＩＴＥ　ＢＰ－８６９）である請求の範囲第５項記載のＦＫＩ－４４２９物質の製造方法。 The FKI- according to claim 5, wherein the microorganism is Penicillium sp. FKI-4429 (Accession number (domestic deposit) NITE P-869, Accession number (international deposit) NITE BP-869). 4429 Substance manufacturing method.
  7. 　ペニシリウム・エスピー（Ｐｅｎｉｃｉｌｌｉｕｍ　ｓｐ．）ＦＫＩ－４４２９（受託番号（国内寄託）　ＮＩＴＥ　Ｐ－８６９，受託番号（国際寄託）　ＮＩＴＥ　ＢＰ－８６９）株。 Penicillium sp. FKI-4429 (Accession number (domestic deposit) NITE P-869, Accession number (international deposit) NITE BP-869).
  8. 　下記式［Ｉ］で表されるＦＫＩ－４４２９－１物質と下記式［ＩＩ］で表されるＦＫＩ－４４２９－２物質と下記式［ＩＩＩ］で表されるＦＫＩ－４４２９－３物質と下記式［ＩＶ］で表されるＦＫＩ－４４２９－４物質との少なくともいずれかひとつと、アミノグリコシド系抗生物質とを組み合わせたことを特徴とする抗菌剤。
    Figure JPOXMLDOC01-appb-C000009
    Figure JPOXMLDOC01-appb-C000010
    Figure JPOXMLDOC01-appb-C000011
    Figure JPOXMLDOC01-appb-C000012
         FKI-4429-1 substance represented by the following formula [I], FKI-4429-2 substance represented by the following formula [II], FKI-4429-3 substance represented by the following formula [III], and the following formula An antibacterial agent comprising a combination of at least one of the FKI-4429-4 substance represented by [IV] and an aminoglycoside antibiotic.
    Figure JPOXMLDOC01-appb-C000009
    Figure JPOXMLDOC01-appb-C000010
    Figure JPOXMLDOC01-appb-C000011
    Figure JPOXMLDOC01-appb-C000012
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* 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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