JPH01299280A - Novel antibiotic substance h9 and production thereof - Google Patents
Novel antibiotic substance h9 and production thereofInfo
- Publication number
- JPH01299280A JPH01299280A JP12664288A JP12664288A JPH01299280A JP H01299280 A JPH01299280 A JP H01299280A JP 12664288 A JP12664288 A JP 12664288A JP 12664288 A JP12664288 A JP 12664288A JP H01299280 A JPH01299280 A JP H01299280A
- Authority
- JP
- Japan
- Prior art keywords
- culture
- antibiotic
- growth
- antibiotic substance
- medium
- 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.)
- Granted
Links
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Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、真菌感染症の治療剤として有用な新規抗生物
質H9およびその製造法に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel antibiotic H9 useful as a therapeutic agent for fungal infections and a method for producing the same.
従来、真菌感染症の治療剤としてはアンホテリシンB1
ナイスタチン、トリフマイシン、グリセオフルビン、ビ
ロールニドリン、クロトリマゾール、硝酸ミコサゾール
等約20種類あるが、効力および毒性の点に問題がある
。Conventionally, amphotericin B1 has been used as a treatment for fungal infections.
There are about 20 types, including nystatin, tryfmycin, griseofulvin, virolnidoline, clotrimazole, and micosazole nitrate, but they have problems in terms of efficacy and toxicity.
本発明は真菌感染症の治療剤として高活性、低港性の新
規抗生物質を提供することを目的とするものである。The object of the present invention is to provide a novel antibiotic with high activity and low potency as a therapeutic agent for fungal infections.
本発明者らは新規な抗生物質の探索を目的として多数の
微生物を土壌中より分離し、その産生ずる抗生物質を分
離し、その生物学的性質を調べたところ、ストレプトミ
セス属に属する微生物の培養物中にカンジダ・アルビカ
ンスその他の病原性真菌に対して抗菌活性を示す文献未
載の新規抗生物質が生産されることを見出した。The present inventors isolated a large number of microorganisms from soil for the purpose of searching for new antibiotics, isolated the antibiotics they produced, and investigated their biological properties. We have discovered that a novel antibiotic, which has not yet been described in any literature, is produced in culture that exhibits antibacterial activity against Candida albicans and other pathogenic fungi.
この抗生物質を該培養物から単離し、その理化学的性質
を調べた結果、後述の式■の構造式を有する新規物質で
あることを確認しこの抗生物質をH9と命名した。This antibiotic was isolated from the culture and its physicochemical properties were investigated. As a result, it was confirmed that it was a new substance having the structural formula of formula (2) described below, and this antibiotic was named H9.
すなわち本発明は、下記式
で表わされる抗生物質H9およびその製造法を提供する
ものである。That is, the present invention provides antibiotic H9 represented by the following formula and a method for producing the same.
まず本発明において用いる微生物は新規抗生物質H9の
生産能を有するストレプトミセス属に属する菌種である
。First, the microorganism used in the present invention is a species belonging to the genus Streptomyces that has the ability to produce the novel antibiotic H9.
その−例としてストレプトミセス sp、 PH317
と称する微生物が前記の特性を有する新菌株で、本発明
に有効に利用しうる。ストーブ)1セスBp、 FH3
17C以下単にIFH317株という)は工業技術院微
生物工業技術研究所に寄託申請しく昭和63年4月30
日)、微工研菌寄第10012号として受託された。For example, Streptomyces sp, PH317
A new strain of microorganism called . Stove) 1 cess Bp, FH3
17C (hereinafter simply referred to as strain IFH317) was submitted to the Institute of Microbiology, Agency of Industrial Science and Technology for deposit on April 30, 1986.
(Japan), and was entrusted with the Microtechnical Research Institute No. 10012.
FH317株は下記の菌学的性質を有する。Strain FH317 has the following mycological properties.
1、形態学的性質
気菌糸はイースト・麦芽寒天培地、スターチ・無機塩寒
天培地、チロシン寒天培地などで良好に着生する。分岐
法は単純分岐で車軸分岐は認めら減ない。気菌糸先端の
形状は直状または屈曲状であり3〜10個の短い胞子連
鎖が認められる。胞子の表面構造は平滑であり形状は橢
円形または円筒形で大きさは0.6〜0.7 X O,
9〜1.0μmである。胞子のう、菌核、菌糸束などの
構造物は認められない。1. Morphological properties Aerial mycelium grows well on yeast/malt agar, starch/inorganic salt agar, tyrosine agar, etc. The branching method is simple branching, and axle branching is not allowed. The shape of the aerial mycelium tip is straight or bent, and short chains of 3 to 10 spores are observed. The surface structure of the spore is smooth, the shape is oval or cylindrical, and the size is 0.6 to 0.7 × O,
It is 9 to 1.0 μm. Structures such as sporangia, sclerotia, and hyphal bundles are not observed.
〔各種培地上における性質(28°C,2週間培養後観
察)〕(1)イースト・麦芽寒天培地(工SP培地A2
に準じる)
生育は普通。気菌糸着生は良好で灰色。発育裏面は黄褐
色から暗褐色。可溶性色素は認められない。[Properties on various media (28°C, observation after 2 weeks of culture)] (1) Yeast/malt agar medium (Technical SP medium A2)
) Growth is normal. Aerial mycelial growth is good and gray in color. The underside of the growth is yellowish brown to dark brown. No soluble dyes are observed.
(2オートミール寒天培地(工sp培地A3に準じる)
生育はやや貧弱。気菌糸着生はやや不良で白色から灰色
。発育裏面は特徴のない淡黄色。(2 Oatmeal agar medium (according to engineering sp medium A3) Growth is rather poor. Aerial mycelial attachment is somewhat poor and white to gray in color. The underside of growth is pale yellow with no characteristics.
可溶性色素は認められない。No soluble dyes are observed.
(Jスターチ・無機塩寒天培地CISP培地潟4に準じ
る)
生育は普通。気菌糸着生は良好で灰色。発育裏面は特徴
のない淡黄色または黄褐色。可溶性色素は認められない
。(According to J starch/inorganic salt agar medium CISP medium Gataka 4) Growth is normal. Aerial mycelial growth is good and gray in color. The underside of the growth is featureless and pale yellow or yellowish brown. No soluble dyes are observed.
(→グリセリン・アスパラギン寒天培地(工SP培地屋
5に準じる)
生育は貧弱6気菌糸着生はないかまたは非常に不良。可
溶性色素は認められない。(→Glycerin/asparagine agar medium (according to Engineering SP Medium Store 5) Growth is poor.6 Aerial mycelium is absent or very poor. No soluble pigments are observed.
(団グルコース・アスパラギン寒天培地生育は貧弱。気
菌糸着生はないかまたは非常に不良。可溶性色素は認め
られない。(Glucose-asparagine agar medium growth is poor. Aerial mycelium is absent or very poor. No soluble pigments are observed.
(eチロシン寒天培地(工SF培地A7に準じる)生育
は普通。気菌糸着生は良好で灰色。発育裏面は暗褐色。(e) Growth on tyrosine agar medium (according to SF medium A7) is normal. Aerial mycelial attachment is good and gray. The underside of growth is dark brown.
可溶性色素は認められない。No soluble dyes are observed.
(カシュクロース・硝酸塩寒天培地 生育は貧弱。気菌糸着生は不良で白色から明るい灰色。(Kashucrose/nitrate agar medium Growth is poor. Aerial mycelial growth is poor and the color ranges from white to light gray.
可溶性色素は認められない。No soluble dyes are observed.
(8)栄養寒天培地
生育は普通。気菌糸着生は不良で白色から灰色。発育裏
面は特徴のない淡黄色。可溶性色素は認められない。(8) Growth on nutrient agar medium is normal. Aerial mycelial growth is poor and white to gray in color. The underside of the growth is pale yellow with no characteristics. No soluble dyes are observed.
2、生理学的性質
(1)生育温度範囲(トリプトン・イースト液体培地、
温度勾配装置使用、7日間)
生育可能温度:12°C〜40℃ 生育適温:22℃
〜32℃
(2)ゼラチンの液化(グルツース番ペプトン・ゼラチ
ン培地、28℃、2週間)
陽性
(3脱脂乳の凝固、ペプトン化(10%スキムミルク、
28℃、2週間)
ペプトン化:陽性 凝固:陰性
(→メラノイト°色素の生成
チロシン寒天培地:陰性
ペプトン・イースト・鉄寒天培地:陰性トリプトン・イ
ースト液体培地:陰性
(S炭素源の利用性(プリドハム・ゴトリーブ寒天培地
、炭素源1%、28°C,2週間)陽性:グルツース、
フラクトース、キシロース、マンニトール、ラフイノー
ス
擬陽性:アラビノース
陰性:ラムノース、イノシトール、シュクロース
(6)耐塩性(イースト・麦芽寒天培地にN&OA’を
添加、28°C,2週間)
Na()/ l 9%まで生育、NILOA’ 13%
では生育しない。2. Physiological properties (1) Growth temperature range (tryptone yeast liquid medium,
(Using temperature gradient device, 7 days) Possible growth temperature: 12°C to 40°C Suitable growth temperature: 22°C
~32℃ (2) Liquefaction of gelatin (Glutose No. peptone gelatin medium, 28℃, 2 weeks) Positive (3) Coagulation of skim milk, peptonization (10% skim milk,
28℃, 2 weeks) Peptonization: Positive Coagulation: Negative (→ melanoid production・Gotlieb agar medium, carbon source 1%, 28°C, 2 weeks) Positive: Glutose,
Fructose, xylose, mannitol, raffinose False positive: Arabinose negative: Rhamnose, inositol, sucrose (6) Salt tolerance (addition of N&OA' to yeast/malt agar medium, 28°C, 2 weeks) Na()/l up to 9% Growth, NILOA' 13%
It won't grow.
上に記した形態学的および生理学的性質に加え全菌体の
加水分解物からLL−ジアミノピメリン酸が検出されI
FH317株は明らかにストレプトミセス属に属する菌
株と認められる。In addition to the morphological and physiological properties described above, LL-diaminopimelic acid was detected in the hydrolyzate of whole bacterial cells.
Strain FH317 is clearly recognized as a strain belonging to the genus Streptomyces.
IPH317株の示す諸性状をパージエイズ・マニュア
ルーオプ・デターミネイティブ・バクテリオロジ−(第
8版、1974年);ザ・アクチノミセテス第2巻(ワ
ックスマン著、1962年)およびイー・ビー・シャー
リングらの報告(インターナショナル・ジャーナル・オ
ブ・システマテイツク・バクテリオロジー第18巻、1
968年、第69ページ、同第18巻、1968年、第
279ページ、同第19巻、1969年、第391ペー
ジ、同第22巻、1972年、第265ページ)に記載
されている既知のストレプトミセス属菌種とその性状を
比較すると比較的近似する菌種としてストレプトミセス
・ハルステデイ(Streptomyaeshalst
edii )およびストレプトミセス・カテヌラエ(S
treptomycsa oatenulaa )の2
菌種が挙げられる。以上の2菌種はメラノイド色素の生
産が認められず胞子連鎖が短く(10個以下)、胞子表
面が平滑状で胞子鎖形態が直状または屈曲状という点で
近似している。ストレプトミセス・ハルステデイは気菌
糸色調が灰色、発育裏面が特徴のない灰黄色から黄褐色
である点でも本菌に近似しているが胞子鎖形態が屈曲状
が主体である点、耐塩性がNhO1≧7%(10%〉)
である点、および炭素源としてマンニトールとラフィノ
ースを利用しない点で本菌と異なる。The properties of the IPH317 strain are described in Purging Aids Manual-Op Determinative Bacteriology (8th edition, 1974); The Actinomycetes Volume 2 (Waxman, 1962) and E.B. Shearing et al. Report (International Journal of Systematic Bacteriology Vol. 18, 1)
968, p. 69, vol. 18, 1968, p. 279, vol. 19, 1969, p. 391, vol. 22, 1972, p. 265). When comparing Streptomyces species and their characteristics, one species that is relatively similar is Streptomyces halstedi (Streptomyeshalst).
edii) and Streptomyces catenulae (S
2 of treptomycsa oatenulaa)
Examples include bacterial species. The above two bacterial species are similar in that they do not produce melanoid pigments, have short spore chains (10 or less), have smooth spore surfaces, and have straight or curved spore chain morphology. Streptomyces halsteadei is similar to this fungus in that its aerial hyphae are gray in color and the underside of its growth is a featureless gray-yellow to yellowish-brown color, but its spore chain morphology is mainly curved, and its salt tolerance is NhO1. ≧7% (10%>)
This bacterium differs from this bacterium in that it does not use mannitol and raffinose as carbon sources.
ストレプトミセス・カテヌラエは耐m性がNaat≧1
0%(13%〉)である点、および炭素源の利用性がキ
シレースを除いて一致している点で本菌に近似している
。しかしながら気菌糸の色調が緑色から灰緑色、発育裏
面が灰黄色から灰緑茶色である点で本菌と異なる。Streptomyces catenulae has m resistance of Naat≧1
It is similar to this bacterium in that it is 0% (13%>) and that the availability of carbon sources is the same except for xylase. However, it differs from this fungus in that the color of the aerial mycelium ranges from green to gray-green, and the underside of growth ranges from gray-yellow to gray-green-brown.
以上IFH317株はストレプトミセス・ハルステデイ
およびストレプトミセス・カテヌラエに近似する点もあ
るが異なる点も認められ本菌は上記2菌種のいずれに属
させるのも妥当ではない0
したがって本菌をストレプトミセス属に属する別の菌種
と認めストレプトミセス ip、 1FH317(St
reptomyaes sp、 IFH317)と命名
した。As described above, although the IFH317 strain is similar to Streptomyces halsteadii and Streptomyces catenulae, there are also differences, and it is not appropriate to assign this bacterium to either of the above two bacterial species. Streptomyces ip, 1FH317 (St
reptomyaes sp, IFH317).
本発明の抗生物質H9は、上記菌株を栄養源含有培地に
接種し、好気的に培養することにより製造される。抗生
物質H9生産菌としては上記菌株に限らず、ストレプト
ミセス属に属し、抗生物質H9を生産する能力を有する
ものであれば、すべて本発明に使用することができる。Antibiotic H9 of the present invention is produced by inoculating the above strain into a nutrient-containing medium and culturing it aerobically. The antibiotic H9-producing bacteria are not limited to the above-mentioned strains, but any strain that belongs to the genus Streptomyces and has the ability to produce antibiotic H9 can be used in the present invention.
次に、抗生物質H9の製造における菌株の培養について
説明する。Next, culturing of bacterial strains in the production of antibiotic H9 will be explained.
H9を生産する菌の培養に際しては、炭素源として例え
ばグルコース、フラクトース、デンプン、デキストリン
、グリセリン、糖蜜、水飴、油脂類、有機酸類などの資
化し得る有機炭素化合物が、窒素源としては例えば大豆
粉、綿実粉、コーンスチープリカー、カゼイン、ペプト
ン、酵母エキス、肉エキス、胚芽、尿素、アミノ酸、ア
ンモニウム塩などの有機窒素化合物や無機窒素化合物が
、また塩類としては例えばナトリウム塩、カリウム塩、
カルシウム墳、マグネシウム塩、リン酸塩などの無機塩
類が単独あるいは適宜組合せて使用される。さらに必要
に応じて、鉄塩、銅塩、亜鉛塩、コバルト塩などの重金
属、ビオチン、ビタミンB1などのビタミン類、その他
菌の発育を助け、H9の生産を促進するような有機物や
無機物を適宜添加してもよい。また、シリコーンオイル
、ポリアルキレングリコールエーテルなどの消泡剤や界
面活性剤を培地に加えてもよい。When culturing the bacteria that produce H9, assimilated organic carbon compounds such as glucose, fructose, starch, dextrin, glycerin, molasses, starch syrup, fats and oils, and organic acids are used as the carbon source, and soybean flour as the nitrogen source. organic and inorganic nitrogen compounds such as cottonseed flour, corn steep liquor, casein, peptone, yeast extract, meat extract, germ, urea, amino acids, ammonium salts, and salts such as sodium salts, potassium salts,
Inorganic salts such as calcium salts, magnesium salts, and phosphates may be used alone or in appropriate combinations. Furthermore, if necessary, heavy metals such as iron salts, copper salts, zinc salts, and cobalt salts, vitamins such as biotin and vitamin B1, and other organic and inorganic substances that support the growth of bacteria and promote H9 production are added as appropriate. May be added. Furthermore, antifoaming agents and surfactants such as silicone oil and polyalkylene glycol ether may be added to the medium.
培養法としては、一般の抗生物質の生産に用いられる方
法が採用されるが、液体培養法、特に振とうまたは深部
通気攪拌培養が最適である。As the culture method, methods used in the production of general antibiotics are employed, but liquid culture methods, particularly shaking or deep aeration agitation culture, are most suitable.
培養には好気的条件が適し、培V温度は通常22〜32
°Cが好ましく、培養pHは6〜8であるが、7付近が
好ましい。培養物中のH9の生M!Ikは2〜6日の培
養で充分高くなる。Aerobic conditions are suitable for culturing, and the culture temperature is usually 22-32°C.
°C is preferred, and the culture pH is 6 to 8, preferably around 7. Live M of H9 in culture! Ik becomes sufficiently high after 2 to 6 days of culture.
以上の如く培養物中に蓄積されたH9を培養物中から採
取するためには、後記する本抗生物質の理化学的性質を
利用することによって有利に行われる。In order to collect H9 accumulated in the culture as described above from the culture, it is advantageous to take advantage of the physical and chemical properties of the present antibiotic described below.
すなわち、n 9は培養F液に含有されるので、まず培
養物に濾過助剤を加えて濾過あるいは遠心分離すること
によって、菌体を除去する。得られた培glP液を担体
に接触させて液中の有効成分を吸着させ、次いで溶媒で
有効物質を脱着させ、分別採取する手段が有利に利用さ
れる。That is, since n9 is contained in the culture solution F, the bacterial cells are first removed by adding a filter aid to the culture and performing filtration or centrifugation. Advantageously, a method is used in which the obtained culture medium GlP liquid is brought into contact with a carrier to adsorb the active ingredient in the liquid, and then the active substance is desorbed with a solvent and then fractionated and collected.
クロマトグラフィーの担体としては活性炭、粉末セルロ
ース、吸着性樹脂など化合物の吸着性の差を利用するも
のが有効に用いられる。これら担体から目的とする化合
物を溶出するためには担体の種類、性質によって組み合
せが異なるが、例えば水溶性有機溶媒の含水溶液すなわ
ち含水アセトン、含水アルコール類などを適宜組み合せ
て用いることができる。As carriers for chromatography, active carbon, powdered cellulose, adsorbent resins, and other carriers that utilize differences in adsorption of compounds are effectively used. In order to elute the target compound from these carriers, the combination will differ depending on the type and nature of the carrier, but for example, an appropriate combination of aqueous solutions of water-soluble organic solvents, such as aqueous acetone, aqueous alcohols, etc. can be used.
またこれらのり四マドグラフィーによって得られた抗生
物質を含む粗物質を分取用高速液体クロマ(グラフィー
に付し、精製品を得る事もできる。In addition, a purified product can also be obtained by subjecting the crude substance containing antibiotics obtained by these methods to preparative high-performance liquid chromatography.
さらに詳しく述べるならば、担体として吸着性樹脂例え
ばダイヤイオンHP 20あるいは5P207(三菱化
成工業株式会社製)、アンパライトXAD −2(ロー
ム−アンド・ハース社製、米国)などを用いるとF液中
の抗菌性物質は吸着され、含水アセトンあるいは含水ア
ルコール類などで溶出される。分画された溶出画分は濃
縮できる。In more detail, if an adsorbent resin such as Diaion HP 20 or 5P207 (manufactured by Mitsubishi Chemical Industries, Ltd.) or Amparite XAD-2 (manufactured by Rohm and Haas, USA) is used as a carrier, the Antibacterial substances are adsorbed and eluted with aqueous acetone or aqueous alcohols. The fractionated eluted fraction can be concentrated.
得られた粗物質をさらに精製するためには高速液体クロ
マトグラフィー法(HPI+C)が有効に利用できる。High performance liquid chromatography (HPI+C) can be effectively used to further purify the obtained crude material.
用いられる担体としてはたとえばTSKゲル(トーソー
株式会社製) 、ypAoゲル(山村化学研究所製)な
どが挙げられ移動層としては含水メタノールあるいは含
水アセトニトリルなどを用いることができる。Examples of carriers that can be used include TSK gel (manufactured by Toso Corporation) and ypAo gel (manufactured by Yamamura Kagaku Kenkyusho), and as a mobile phase, water-containing methanol or water-containing acetonitrile can be used.
以上の如くして得られた抗生物質H9は次の物理化学的
性質を有する。The antibiotic H9 obtained as described above has the following physicochemical properties.
■外 観:無色粘稠な液体
■比旋光度: (α)”−461,0°(c O,1ア
七ト二ト リ ル )
■元素分析(0uHuQnとして)
0% H%
実測値 63.63 8.03
理論値 63.70 8.02
■分子fi (IFABマススペクトルによる)319
(MH+グリセリン〕“
■紫外部(trv )吸収スペクトル:アセトニトリル
−水中(第1図参照)
1チ −
λ、aX255nm(11377)
1国 −
■赤外部(工R)吸収スペクトル: KBr H(第2
図参照)
主な吸収を示す(波Wl)
3450.2970,1845,1775゜1275
、 920 cm−’
■1m□核磁気共鳴(NMR) スヘク) ル: 50
MHzsδPT1m %重クロロホルム中
下記のシグナルが認められる(第3図参照)165.6
(s)、 165.2(11)、 143..6(s)
−142,1k)、 72.2(司、 41. f(t
) 、 36.8<a)。■Appearance: Colorless viscous liquid ■Specific optical rotation: (α)''-461,0° (cO, 17tonitrile) ■Elemental analysis (as 0uHuQn) 0% H% Actual value 63 .63 8.03 Theoretical value 63.70 8.02 ■Molecular fi (according to IFAB mass spectrum) 319
(MH + Glycerin) ■ Ultraviolet (trv) absorption spectrum: Acetonitrile-water (see Figure 1) 1st - λ, aX 255 nm (11377) 1st country - ■ Infrared (trv) absorption spectrum: KBr H (second
(See figure) Shows main absorption (wave Wl) 3450.2970,1845,1775°1275
, 920 cm-' ■1m□Nuclear magnetic resonance (NMR) size: 50
MHzsδPT1m The following signal is observed in % deuterated chloroform (see Figure 3) 165.6
(s), 165.2(11), 143. .. 6(s)
-142,1k), 72.2(Tsukasa, 41.f(t
), 36.8<a).
25.2(d)、 24.0(t)、 21.3(q)
、 15.7(q)。25.2(d), 24.0(t), 21.3(q)
, 15.7(q).
10、1 (q)
8ニ一重線、d:二重線、t:三重線、q:四重線
■高速液体クロマトグラフィー(HPI、O)カラム:
カプセルバック0ts(4,6φ×250m、資生堂製
)
移動相: 0HsON−HzO(1: 1 ) 、流速
:0.8m11分、Rt= 15.5 C分)
■呈色反応:
陰 性:ニンヒドリン、ドラーゲンドルフ、坂口、ライ
ドン・スミス、レゾルシ
ン−硫酸、過マンガン酸カリウム
O溶解性:
可溶:メタノール、アセトニトリル、クロロホルム、酢
酸エチル
難溶:水
O酸性、中性、塩基性の区別:
中性
H9は各種スペクトルを検討した結果、前記式■の構造
を有すると決定された。この構造に一致する既知物質は
報告されていないのでH9は新規物質であると決定した
。10, 1 (q) 8 doublet, d: doublet, t: triplet, q: quartet ■High performance liquid chromatography (HPI, O) column:
Capsuleback 0ts (4.6φ x 250m, manufactured by Shiseido) Mobile phase: 0HsON-HzO (1:1), flow rate: 0.8m 11 minutes, Rt = 15.5 C minutes) Color reaction: Negative: Ninhydrin, Dragendorff, Sakaguchi, Lydon Smith, Resorcin - Sulfuric acid, potassium permanganate O Solubility: Soluble: methanol, acetonitrile, chloroform, ethyl acetate Poorly soluble: Water O Distinction between acidic, neutral and basic: Neutral As a result of examining various spectra, H9 was determined to have the structure of the above formula (2). Since no known substance matching this structure has been reported, H9 was determined to be a new substance.
次にH9の各FJI生物に対する抗菌スペクトルを第1
表に示す(液体培地希釈法による)第 1 表
IT工MMO144’ I 25
IT1MMO171t 50
# Yu1200 # >100
D 25
アスペルギルス・オリザエ
100エシエリヒア・フリーN工HJ> 100サラ
に、H9のマウスを用いた急性毒性試験では200q/
Kpの腹腔内投与で異常を認めなかった。Next, the antibacterial spectrum of H9 against each FJI organism was determined as follows.
Table 1 (based on liquid medium dilution method)
100 Escherichia Free N Engineering HJ > 100 Sarah, acute toxicity test using H9 mice showed 200q/
No abnormalities were observed after intraperitoneal administration of Kp.
次に実施例を挙げて本発明をさらに具体的に説明する。 Next, the present invention will be explained in more detail with reference to Examples.
なお、培地における7寸−セント番ま特にことわりのな
い限り重量/容量%を示す。In addition, unless otherwise specified, 7-cent numbers in the culture medium are shown as weight/volume %.
実施例 1
pa317株の斜面培養から一白金耳を1001IIt
の種培地(グルコース1.0%、ポリペプトン0.2%
、ビーフエキス0.1%、イーストエキス0.1%)を
入れた5 00 rsl容の三角フラスコに接種し、2
7°Cで2日間振とう培養して種培養液を得た。この種
培養液1400mjを、140/の生産培地(ボテトス
々−チ0.7%、グルコース0.7%、SBM 1.0
%、イーストエキス0.35%、塩化ナトリウム0.2
%、炭酸カルシウム0.3%)を入れた200/容ジヤ
ー7アーメンターに接種し、27〜30℃、66時間通
気攪拌培1!(通気量80〜l 101/ I!Iin
、攪拌20 Or、p、m)を行った。培養液をpH3
に調整後セライト1.5kを加えてフィルタープレスで
濾過し、菌体を除去し、F液110jを得た。Example 1 One platinum loop was collected from a slant culture of pa317 strain.
Seed medium (glucose 1.0%, polypeptone 0.2%
, beef extract 0.1%, yeast extract 0.1%) into a 500 rsl Erlenmeyer flask, and
A seed culture solution was obtained by culturing with shaking at 7°C for 2 days. 1400 mj of this seed culture solution was mixed with 140 mj of production medium (Botetosu 0.7%, glucose 0.7%, SBM 1.0
%, yeast extract 0.35%, sodium chloride 0.2
%, calcium carbonate 0.3%) into a 200/vol jar 7-armentor, and cultured with aeration at 27-30°C for 66 hours. (Airflow amount 80~l 101/I!Iin
, stirring 20 Or, p, m). Adjust the culture solution to pH 3
After adjustment, 1.5k of Celite was added and filtered with a filter press to remove bacterial cells to obtain Liquid F 110j.
このF液を41の吸着型合成樹脂ダイヤイオンHP20
(三菱化成社製)を充填したカラムに通した後、水でカ
ラムを洗浄し、次いで50%メタノール水で溶出した。This F liquid was added to 41 adsorption type synthetic resin Diamond Ion HP20.
(manufactured by Mitsubishi Kasei Corporation), the column was washed with water, and then eluted with 50% methanol water.
溶出液を減圧濃縮し、残渣24. S Pを得た。この
残渣をメタノールで抽出し、抽出液を減圧濃縮し、粗物
質17.5 Fを得た。粗物質を分取用逆相高速液体ク
ロマトグラフィー〔カラム: YMOS −343(山
村化学研究所製)、移動相50%ア七トニトリル水〕に
付し、活性画分を得た。この両分を減圧濃縮し、無色粘
稠な液体の抗生物質u9 2.05Pを得た。The eluate was concentrated under reduced pressure to obtain a residue 24. I got SP. This residue was extracted with methanol, and the extract was concentrated under reduced pressure to obtain 17.5 F of crude material. The crude substance was subjected to preparative reverse-phase high performance liquid chromatography [column: YMOS-343 (manufactured by Yamamura Kagaku Kenkyusho), mobile phase 50% aqueous a7tonitrile] to obtain an active fraction. Both portions were concentrated under reduced pressure to obtain a colorless viscous liquid antibiotic u9 2.05P.
〔発明の効果〕
本発明のH9は放線菌によって生産される新規抗生物質
であり、毒性が低くカンジダに対する抗菌活性を有する
ので臨床用医薬品たとえば真菌症め治療剤として有用で
ある。[Effects of the Invention] H9 of the present invention is a new antibiotic produced by actinomycetes, and has low toxicity and antibacterial activity against Candida, so it is useful as a clinical drug, such as a therapeutic agent for fungal diseases.
第1図は抗生物質H9の紫外部吸収スペクトル、第2図
は同抗生物質の赤外部吸収スペクトル、第3図は11C
核磁気共鳴(NMR)スペクトルである。Figure 1 is the ultraviolet absorption spectrum of antibiotic H9, Figure 2 is the infrared absorption spectrum of the same antibiotic, and Figure 3 is 11C.
This is a nuclear magnetic resonance (NMR) spectrum.
Claims (1)
る菌株を栄養培地にて培養し、培養物から抗生物質H9
を採取することを特徴とする新規抗生物質H9の製造法
。[Claims] 1. A novel antibiotic H9 represented by the following formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are available▼. 2. A strain belonging to the genus Streptomyces that produces the antibiotic H9 is cultured in a nutrient medium, and the antibiotic H9 is extracted from the culture.
A method for producing a novel antibiotic H9, which comprises collecting .
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12664288A JPH0822858B2 (en) | 1988-05-24 | 1988-05-24 | Novel antibiotic H9 and method for producing the same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12664288A JPH0822858B2 (en) | 1988-05-24 | 1988-05-24 | Novel antibiotic H9 and method for producing the same |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH01299280A true JPH01299280A (en) | 1989-12-04 |
JPH0822858B2 JPH0822858B2 (en) | 1996-03-06 |
Family
ID=14940254
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP12664288A Expired - Lifetime JPH0822858B2 (en) | 1988-05-24 | 1988-05-24 | Novel antibiotic H9 and method for producing the same |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0822858B2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007039749A2 (en) * | 2005-10-06 | 2007-04-12 | Aston University | Antibacterial pyrrols |
-
1988
- 1988-05-24 JP JP12664288A patent/JPH0822858B2/en not_active Expired - Lifetime
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007039749A2 (en) * | 2005-10-06 | 2007-04-12 | Aston University | Antibacterial pyrrols |
WO2007039749A3 (en) * | 2005-10-06 | 2008-05-08 | Univ Aston | Antibacterial pyrrols |
Also Published As
Publication number | Publication date |
---|---|
JPH0822858B2 (en) | 1996-03-06 |
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