CN112955140A - 包含雌马酚作为有效成分的针对肠道细菌的抗菌剂 - Google Patents
包含雌马酚作为有效成分的针对肠道细菌的抗菌剂 Download PDFInfo
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Abstract
提供一种针对会在人体中引起感染症的艰难梭菌等肠道细菌的抗菌药。一种针对肠道细菌的抗菌剂,其包含雌马酚作为有效成分。
Description
技术领域
本发明涉及针对肠道细菌、特别是艰难梭菌的抗菌剂。
背景技术
艰难梭菌(C.difficile)是症状为腹泻和/或腹痛、有时会致人死亡的艰难梭菌感染症(CDI)的致病菌。艰难梭菌感染症作为院内感染症已成为问题(参照非专利文献1)。
对于艰难梭菌(C.difficile)感染症,使用甲硝唑等抗原虫药、万古霉素等抗生素作为抗菌药,但是,当艰难梭菌形成芽胞时,这些抗菌药的效果会降低。
产气荚膜梭菌(C.perfringens)是一种人体常驻菌,在家畜、鱼类中也可检出。产气荚膜梭菌已知是一种耐热、会导致食物中毒的致病菌。
脆弱拟杆菌(B.fragilis)是一种人体常驻菌,也存在产毒素型的菌。脆弱拟杆菌据说会导致大肠癌。
雌马酚是大豆的代谢终产物,是通过肠道细菌由大豆异黄酮生物合成而成的。雌马酚的结构与作为女性激素的雌激素类似,因此已经建立了大豆源雌马酚的制造方法(参照专利文献1),并且被作为对骨强化等有用的补充剂的有效成分利用(参照专利文献2)。
现有技术文献
专利文献
专利文献1:日本特开2017-18120号公报
专利文献2:日本特开2013-184959号公报
非专利文献
非专利文献1:神谷茂、MODERN MEDIA、第56卷第10期2010[話題の感染症]([话题之感染症])pp.233-241
发明内容
发明要解决的问题
本发明的目的在于,提供针对会在人体中引起感染症的艰难梭菌等肠道细菌的抗菌药。
用于解决问题的方案
本发明人调查了在人的肠道内合成的雌马酚对肠道细菌的影响。其结果是,确认雌马酚浓度依赖性地抑制艰难梭菌等肠道细菌的生长,还抑制艰难梭菌的芽胞形成,发现能够使用雌马酚作为艰难梭菌等肠道细菌的抗菌剂,从而完成了本发明。
即,本发明如下所述。
[1]一种针对肠道细菌的抗菌剂,其包含雌马酚作为有效成分。
[2]根据[1]的抗菌剂,其中,肠道细菌选自由艰难梭菌(Clostridioidesdifficile)、产气荚膜梭菌(C.perfringens)及脆弱拟杆菌(B.fragilis)组成的组。
[3]根据[1]或[2]的抗菌剂,其抑制艰难梭菌的生长且抑制艰难梭菌的芽胞形成。
[4]一种艰难梭菌感染症的预防或治疗剂,其包含[1]~[3]中任一项的抗菌剂。
[5]一种肠道调整剂,其包含雌马酚作为有效成分。
[6]根据[5]的肠道调整剂,其中,肠道调整剂缓解肠道细菌性腹泻和/或腹痛的症状。
[7]一种大肠癌预防和/或治疗剂,其包含雌马酚作为有效成分。
本说明书包含了作为本申请的优先权基础的、日本专利申请号2018-203055号的公开内容。
发明的效果
艰难梭菌通过形成芽胞而对抗菌药显示出抗性,另外通过分泌毒素而引起感染症。另外,艰难梭菌会引起院内感染。雌马酚能够浓度依赖性地抑制艰难梭菌的生长、并且能够抑制艰难梭菌的芽胞形成,因此能够作为艰难梭菌的抗菌药使用,还能够防止艰难梭菌的院内感染。
附图说明
图1为示出雌马酚对艰难梭菌027株的生长抑制效果的图。
图2为示出大豆异黄酮对艰难梭菌生长的影响的图。
图3为示出雌马酚对4个艰难梭菌菌株的生长抑制效果的图。
图4为示出雌马酚对其它菌种的生长抑制效果的图。
图5为示出雌马酚对艰难梭菌形态的影响的图。
图6为示出雌马酚对艰难梭菌芽胞形成的抑制效果的图。
具体实施方式
以下详细说明本发明。
本发明为一种针对肠道细菌的抗菌剂,其包含雌马酚(Equal、4’,7-异黄烷二酚)作为有效成分。
本发明中,“抗菌”并不是指杀灭细菌,而是指抑制或阻碍细菌的生长及增殖,与“杀菌”、“除菌”不同。
雌马酚为大豆的代谢终产物,是通过肠道细菌由大豆异黄酮生物合成的。
雌马酚的化学式为C15H14O3,结构式如以下所示。
存在能够在肠道内合成雌马酚的人和不能合成的人,取决于肠道菌群中是否具有雌马酚产生菌。
雌马酚对部分肠道细菌具有抗菌活性。作为雌马酚对其具有抗菌活性的肠道细菌,可列举艰难梭菌(C.difficile(Clostridioides difficile),CD)、产气荚膜梭菌(C.perfringens(Clostridium perfringens))、脆弱拟杆菌(B.fragilis(Bacteroidesfragilis))等,尤其对艰难梭菌有效。
已知艰难梭菌是作为代表性的院内感染症的艰难梭菌感染症(Clostridioidesdifficile infection,CDI)的原因。艰难梭菌感染症为消化道感染症,引起肠炎,伴有腹泻、腹痛的症状,有时还伴有发热、白细胞增多,严重时甚至会致死。艰难梭菌会形成芽胞,当CDI患者的排泄物中包含艰难梭菌和/或其芽胞、特别是包含芽胞(spore)时,会通过排泄物而残存于盥洗室、床、地板等医院内环境中,有时会引发院内感染这一严重问题。对于艰难梭菌,使用甲硝唑等抗原虫药、万古霉素等抗生素作为抗菌药,但是,当形成芽胞时,对抗菌药显示抗性,这些抗菌药的效果会降低。残存的芽胞会出芽而再次引起艰难梭菌感染症。
产气荚膜梭菌(C.perfringens(Clostridium perfringens))也被称为魏氏梭菌,存在于人、家畜、鱼等动物的肠道内,释放作为毒素的肠毒素而引起食物中毒。产气荚膜梭菌广泛分布于土壤、河川、海洋等中,因此容易混入到食品、烹调器具中,另外在芽胞状态下具有耐热性,因此容易引起食物中毒。而且,据报道产气荚膜梭菌还与老化、癌症等有关。
脆弱拟杆菌(B.fragilis(Bacteroides fragilis))为存在于人的肠道内的专性厌氧性革兰氏阴性杆菌,不形成芽胞。当侵入血管、腹腔内时,有时会引起感染症。据报道,脆弱拟杆菌与大肠癌的发病有关。
雌马酚浓度依赖性地抑制上述肠道细菌、特别是艰难梭菌的生长,还抑制芽胞的形成。通过抑制艰难梭菌在肠道内生长,能够改善、预防艰难梭菌感染症。另外,通过抑制艰难梭菌在肠道内生长,从而能够防止艰难梭菌感染症通过院内感染等而扩散。进一步地,雌马酚能够抑制肠道内的艰难梭菌的芽胞形成,因此能够预防艰难梭菌感染症通过芽胞而扩散。
雌马酚对于肠道菌群中不存在产雌马酚菌的被检体、及存在产雌马酚菌的被检体有用。
关于雌马酚对肠道细菌是否具有抗菌活性这一点,可以通过以一定的菌量培养肠道细菌、向其培养基中加入各浓度的雌马酚并继续进行培养并确认对生长的影响来调查。培养可以在例如厌氧条件下于30~40℃下进行。
雌马酚是以大豆中所含的大豆苷(daidzin)为起始物质、通过肠道细菌的作用而经由大豆苷→大豆苷元→二氢大豆苷元→雌马酚的途径而合成的。可以使用参与这些反应的细菌、由细菌提取的酶来合成雌马酚。雌马酚的制造方法在例如日本特开2017-205117号公报、日本特开2017-18120号公报、日本特开2013-188220号公报、WO2009/084603等中有记载,可以按照这些记载来制造。
雌马酚可以为合成品或通过发酵而得到者中的任一种。作为通过发酵而得到者,只要所发酵的材料包含大豆苷元则可以为任何材料,例如为源自大豆和/或大豆胚轴的材料,可列举含雌马酚的大豆胚轴发酵物、含雌马酚的大豆胚轴提取物发酵物、含雌马酚的大豆发酵物、含雌马酚的大豆提取物发酵物等发酵物中的雌马酚。
本发明的包含雌马酚作为有效成分的针对肠道细菌的抗菌剂可以通过应用于医院内的设施、设备来防止由艰难梭菌、产气荚膜梭菌或脆弱拟杆菌所致的污染的扩散,例如,还能够抑制艰难梭菌的生长、防止艰难梭菌感染症的扩散。这种情况下,可以制成包含雌马酚10μg/mL~100g/mL的水分散性粉剂、液剂、油剂、粉剂、粒剂、溶胶剂(悬浮剂)、凝胶剂等剂型而使用。
另外,本发明的包含雌马酚作为有效成分的针对肠道细菌的抗菌剂可以作为药物组合物而给药于被艰难梭菌、产气荚膜梭菌或脆弱拟杆菌感染的被检体,例如为艰难梭菌感染症的预防或治疗剂。
另外,包含雌马酚作为有效成分的药物组合物可以作为肠道调整剂来使用。该肠道调整剂可以用于缓解肠道细菌性腹泻和/或腹痛的症状。
还已知雌马酚对其具有抗菌活性的肠道细菌与大肠癌的发病有关。因此,包含雌马酚作为有效成分的药物组合物可以作为大肠癌预防和/或治疗剂来使用。
这些抗菌剂、预防或治疗剂可以包含生理学上可接受的的载体或稀释剂。作为载体,可列举生理盐水、磷酸盐缓冲液、葡萄糖液、缓冲生理盐水等。用于被艰难梭菌、产气荚膜梭菌或脆弱拟杆菌感染的被检体的、用来预防或治疗感染症的药物组合物可以以各种形态来给药。例如,可以以片剂、胶囊剂、颗粒剂、散剂、糖浆剂等形态通过经口给药方式来给药,或者以注射剂、点滴剂、栓剂等形态通过非经口给药方式来给药。给药量根据症状、年龄、体重等而不同,通常,在经口给药时,对于成人为每天约0.01mg~1000mg,可以将这些一次性给药或分成数次而给药。另外,在非经口给药时,可以通过皮下注射、肌肉注射或静脉注射每次给药约0.01mg~1000mg。
本发明还包括包含雌马酚的食品组合物。作为食品组合物,可列举点心类(曲奇、饼干、巧克力、薯片、蛋糕、口香糖、糖果、软糖、馒头、羊羹、布丁、果冻、酸奶、冰淇淋、果子露等)、面包、面条类、米饭类、谷物食品、饮料(液剂、清凉饮料、碳酸饮料、营养饮料、粉末饮料、果汁饮料、乳饮料、果冻饮料等)、汤(粉末、冻干)、味噌汁(粉末、冻干)等。
食品组合物不仅包括通常的食品,还包括具有功能性的食品,例如包括健康食品、功能性标示食品、特定保健用食品、营养功能食品等。在此,特定保健用食品是指:标示出在饮食中出于特定的保健目的而摄取、并且通过该摄取可以期待该保健目的的主旨的食品。这些食品可以带有例如主旨为用于肠道调整的标示、主旨为用于缓解腹泻和/或腹痛的标示。
本发明的食品组合物中,每次摄取中可摄取例如优选0.1mg~30mg、更优选2mg~20mg、进一步优选3mg~10mg的雌马酚。作为雌马酚的1次摄取量的下限值的例子,可列举0.2mg、0.5mg、1mg、2mg、3mg、4mg、及5mg,作为上限值的例子,可列举30mg、20mg、10mg、6mg、5mg,雌马酚的每次的摄取量的优选范围可以通过该上限值和该下限值的组合来表示。
本发明的食品组合物中,雌马酚的每天的摄取量如上所述优选30mg以下。作为雌马酚的每天的摄取量,优选0.1mg~30mg、更优选2mg~20mg、进一步优选3mg~10mg。作为雌马酚的每天的摄取量的下限值的例子,可列举0.2mg、0.5mg、1mg、2mg、3mg、4mg、及5mg,作为上限值的例子,可列举30mg、20mg、10mg、6mg、5mg,雌马酚的每天的摄取量的优选范围可以通过该上限值和该下限值的组合来表示。每天可摄取的雌马酚可以通过1次摄取来进行摄取,也可以分成多次(例如2次、3次、4次、及5次)来摄取。
实施例
通过以下的实施例来具体说明本发明,但是本发明不受这些实施例限定。
[实施例1]雌马酚对艰难梭菌(C.difficile)027株的生长抑制
将艰难梭菌(NAP1/027株)添加到包含100μg/mL、75μg/mL、50μg/mL及25μg/mL的浓度的雌马酚的培养基中(0小时),继续进行培养,确认至培养开始后24小时为止对生长的影响。培养条件均为在厌氧下于35℃实施。
另外,由于雌马酚是溶解于DMSO而使用的,因此,作为对照,还对仅加入了DMSO者进行了测定。
通过测定培养基在600nm下的吸光度(OD600)来调查菌的生长。
将结果示于图1。如图1所示,添加了雌马酚时,艰难梭菌的生长比对照慢,认为受到了雌马酚抑制。另外,随着雌马酚的添加浓度的提高,艰难梭菌的生长速度变慢,因此抑制依赖于雌马酚的浓度。
[实施例2]大豆异黄酮对艰难梭菌(NAP1/027株)生长的影响
雌马酚是在肠道细菌作用下由大豆苷(daidzin,daizine)经由大豆苷元(daidzein)、二氢大豆苷元(dihydro daidzein)而生成的最终产物。通过与实施例1相同的方法测定了雌马酚(100μg/mL、50μg/mL)、大豆苷元(50μg/mL)及二氢大豆苷元(100μg/mL、50μg/mL)对艰难梭菌生长的抑制。
将结果示于图2。如图2所示,添加了大豆苷元、二氢大豆苷元50μg/ml的培养基与对照之间未确认到明显差异,而二氢大豆苷元(dihydrodaidzein)100μg/ml以与雌马酚50μg/ml同等的程度抑制艰难梭菌的生长,雌马酚100μg/ml与其相比抑制程度更大。
[实施例3]用4个艰难梭菌菌株时的生长抑制
通过与实施例1相同的方法,检验了027株以外的艰难梭菌的临床分离株(TUM12745株、TUM12806株及TUM12855株)的生长是否也会受到雌马酚(100μg/mL)的抑制。
将结果示于图3。如图3所示,确认实验中使用的所有菌株均同样受抑制。
[实施例4]用其他菌种时的生长抑制
通过与实施例1相同的方法,检验了艰难梭菌以外的菌类是否受雌马酚(100μg/mL)抑制。
将结果示于图4。如图4所示,对于大肠杆菌(大肠埃希氏菌(E.coli或Escherichiacoli)未观察到影响。对于产气荚膜梭菌(C.perfringens(Clostridium perfringens))和脆弱拟杆菌(B.fragilis(Bacteroides fragilis)),则观察到了影响。特别是脆弱拟杆菌,完全未确认到增殖,在试验结束的52小时的时刻转移到未加入雌马酚的培养基,结果形成了菌落,由此可知仅是生长得到抑制、而不是被杀灭。
[实施例5]对形态的影响(革兰氏染色)
通过与实施例1相同的方法使雌马酚(100μg/mL)进行作用,通过革兰氏染色对艰难梭菌进行染色,由此检验雌马酚对艰难梭菌(NAP1/027株)的形态的影响。
将染色图像示于图5。图5为培养起第8天的革兰氏染色的图像。添加了雌马酚100μg/ml的细胞与对照细胞相比,呈现细长的形态。
[实施例6]芽胞形成抑制
为了检验雌马酚(100μg/mL)对艰难梭菌的芽胞形成的影响,向生长艰难梭菌的培养基中加入雌马酚至饱和状态,对形成的芽胞的数量进行计数。
将结果示于图6。如图6所示,在从第2天起的所有日子中,对照中均形成了较多芽胞,与此相对地,加入了雌马酚的培养基中芽胞少。
产业上的可利用性
本发明的包含雌马酚作为有效成分的抗菌剂对选自由艰难梭菌、产气荚膜梭菌及脆弱拟杆菌组成的组中的微生物具有抗菌作用,例如能够预防或治疗艰难梭菌感染症,能够防止艰难梭菌所致的院内感染。
本说明书中引用的所有出版物、专利及专利申请均通过引用而以原状整合到本说明书中。
Claims (7)
1.一种针对肠道细菌的抗菌剂,其包含雌马酚作为有效成分。
2.根据权利要求1所述的抗菌剂,其中,肠道细菌选自由艰难梭菌(Clostridioidesdifficile)、产气荚膜梭菌(C.perfringens)及脆弱拟杆菌(B.fragilis)组成的组。
3.根据权利要求1或2所述的抗菌剂,其抑制艰难梭菌的生长且抑制艰难梭菌的芽胞形成。
4.一种艰难梭菌感染症的预防或治疗剂,其包含权利要求1~3中任一项所述的抗菌剂。
5.一种肠道调整剂,其包含雌马酚作为有效成分。
6.根据权利要求5所述的肠道调整剂,其中,肠道调整剂缓解肠道细菌性的腹泻和/或腹痛的症状。
7.一种大肠癌预防和/或治疗剂,其包含雌马酚作为有效成分。
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