CN114129588B - 含黄芪提取物的抗菌组合物及其应用 - Google Patents
含黄芪提取物的抗菌组合物及其应用 Download PDFInfo
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Abstract
含黄芪提取物的抗菌组合物及其应用。本发明公开了抗菌组合物，所述抗菌组合物包括美罗培南和中药提取物。当将中药提取物与美罗培南联合用药时具有协同作用，能够显著提高对耐药菌的抑菌效果，且效果优于各自单独用药。本发明为研究中西药联合用药对耐药菌的逆转提供了方向。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及包括美罗培南及含黄芪提取物的抗菌组合物及其应用。
背景技术
美罗培南(meropenem)是一种新型的、人工合成的碳青霉烯类抗生素。碳青霉烯类抗生素具有较广的抗菌谱和抗菌活性，是临床上治疗严重混合感染以及耐药菌感染的有效药物，在临床应用中有较高的治疗效果。其中美罗培南通过抑制细菌细胞壁的合成，对大肠杆菌以及铜绿假单胞菌具有较好的抑制效果。但随着美罗培南在临床实践中频繁而广泛地使用，一些不合理使用的情况也逐渐发生，这在一定程度上导致了美罗培南耐药菌的出现，铜绿假单胞菌就是其中之一。铜绿假单胞菌对美罗培南的耐药性与碳青霉烯类抗菌药物的使用量存在正相关关系。碳青霉烯耐药菌株对其他抗菌药物的耐药率普遍高于碳青霉烯敏感菌株，这使得美罗培南药物的临床治疗效益逐渐降低。为解决此问题，不仅要从规范合理用药入手，还需要研究如何抑制耐药菌。有研究报道治疗耐碳青霉烯类抗生素细菌感染的潜在药物，指出其治疗药物主要有多黏菌素、替加环素、磷霉素及氨基糖苷类。但化学抗菌药容易产生耐药性，研究周期长，同时可能导致多重耐药性细菌(“超级细菌”)的出现。
中药作为一类天然药物，不仅具有低毒副作用，还有低耐药性等优点。有研究指出中药可以通过干扰耐药菌的生化代谢以直接抑制或杀灭耐药菌，或者改善细菌的耐药性以间接抑菌杀菌，以及维护机体平衡以整体调节治疗耐药菌感染。然而，不同的中药或中药提取物对细菌或耐药菌的抑制作用不同，也存在一定局限性。
对于天然药物体外、体内和体内外联合抑菌活性的实验方法而言，不同类别天然药物的适用方法各异，因此，需要采用适当的方法，筛选出适合的针对特定菌群或耐药菌的中药或天然药物，从而针对细菌或耐药菌起到抑菌或杀菌作用。
发明内容
本发明的目的在于提供抗菌组合物，能够对耐药菌起到抑菌或杀菌的作用。
第一方面，本发明提供抗菌组合物，所述抗菌组合物包括美罗培南和中药提取物。
在一些实施方案中，所述中药提取物的原料包括黄芪、淫羊藿和/或女贞子。
在一些实施方案中，所述中药提取物为黄芪的提取物；优选地，所述黄芪的提取物为黄芪多糖。
在一些实施方案中，所述中药提取物为黄芪、淫羊藿和女贞子的提取物；优选地，所述中药提取物为芪贞增免颗粒。
在一些实施方案中，本发明所述芪贞增免颗粒可通过如下方法制得：取黄芪25-30份、淫羊藿15-18份、女贞子15-18份，加水煎煮2-3次，每次1-2小时，合并滤液，浓缩，加乙醇，静置使沉淀，取上清液，回收乙醇并浓缩，加入辅料，制粒，即得。
在一些实施方式中，所述芪贞增免颗粒还可以包含党参、白术、当归、升麻、柴胡、陈皮、甘草等的提取物。
在一些实施方案中，本发明所述芪贞增免颗粒可以是可商购获得的产品。
在一些实施方案中，在所述抗菌组合物中，美罗培南与所述中药提取物的重量份比为(1～8):(1000～4000)。
优选地，美罗培南与所述中药提取物的重量份比为(1～4):(1000～4000)，进一步优选地为(1～2):(1000～4000)，更优选地重量份比为1:1000、1:2000、1:4000、1:8000、2:1000、4:1000、8:1000。
第二方面，本发明提供所述抗菌组合物在制备用于抗菌的药物中的用途。
在一些实施方案中，所述菌为美罗培南耐药菌。
在一些实施方案中，所述耐药菌包括大肠杆菌(Escherichia coli)、铜绿假单胞菌(Pseudomonas aeruginosa)、肺炎克雷伯菌(Klebsiella pneumonia)和鲍氏不动杆菌(Acinetobacter baumannii)；优选地，所述耐药菌为大肠杆菌(Escherichia coli)。
本发明的有益效果
为了消除细菌耐药性，本发明从中药提取物入手，通过制备生长曲线和肉汤微量稀释棋盘法试验，筛选出对美罗培南耐药菌体外抑菌作用较强的中药提取物。结果令人惊喜地发现，黄芪多糖和含黄芪的提取物(芪贞增免颗粒)在联合美罗培南用药时，对美罗培南耐药菌在体外有显著的抑制作用，且效果优于各自单独用药，因而美罗培南与所述黄芪多糖或芪贞增免颗粒联合用药时具有明显的协同作用。每种物质在组合物中的相对用量大大减少，进而减少可能的不良反应和副作用，提高用药安全性，同时还可以增加患者服用的依从性，从而保证疗效。
本发明的黄芪多糖或芪贞增免颗粒与美罗培南抗生素联用具有增效和减毒优势。黄芪多糖或芪贞增免颗粒联合美罗培南抗生素使用能够对美罗培南耐药菌起到抑制作用。本发明为解决美罗培南日趋严重的耐药问题提供了新的研究思路和研发方向。
本发明采用微量肉汤稀释法来研究黄芪多糖或芪贞增免颗粒联合美罗培南用药对美罗培南耐药菌的体外抑制作用，具有重大研究意义，有望对美罗培南治疗重症感染疾病研制新的辅助药提供参考，提高其治疗效益。
附图说明
图1为黄芪多糖(总糖含量65％)联合美罗培南用药的生长曲线。
图2为芪贞增免颗粒联合美罗培南用药的生长曲线。
图3为桑叶提取物联合美罗培南用药的生长曲线。
图4为杜仲提取物联合美罗培南用药的生长曲线。
图5为黄芩苷联合美罗培南用药的生长曲线。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。
实施例1
1.菌种与抗生素
美罗培南耐药大肠杆菌株20a02(由本实验室从鸡场分离保存)。
质控菌株大肠杆菌(ATCC25922)(购于中国兽医药品监察所)。
美罗培南，粉末，纯品。
2.中药提取物
黄芪多糖，总糖含量65％，购自四川金宇植物原料有限公司。
芪贞增免颗粒，购自四川金宇植物原料有限公司。
3.耐药菌与药物的制备
3.1耐药菌的复苏
实验前一天，将耐药菌株划板接种到琼脂培养基上，37℃恒温恒湿培养箱中培养24h备用。
3.2美罗培南药液的配备
用电子分析天平准确称取一定量的美罗培南药粉，加入纯水溶解。配成浓度为2560μg/mL，在超净工作台中，采用注射器吸取药液，透过无菌过滤膜过滤除菌，用2mLEP管分装，-20℃冰箱保存备用。
3.3中药提取物溶液的配制
按照称量实验操作规范，用电子分析天平准确称取40mg中药提取物于10mL EP管中，加入5mL纯水配成浓度为8mg/mL的中药提取物溶液。在超净工作台中用5mL注射器吸取提取物溶液透过无菌过滤膜过滤除菌，并用2mLEP管分装，-20℃冰箱保存备用。
记录生长曲线实验结果，按照上述步骤配制浓度为32mg/mL的中药提取物溶液，除菌后保存备用。
4.美罗培南对耐药大肠杆菌MIC的测定
将冰箱里配制好的美罗培南药液取出，待融化至室温时使用，使用前要摇匀。将美罗培南药液稀释到初浓度为256μg/mL，采用无菌的96孔聚丙烯微量滴定板，根据美罗培南的终浓度质控菌范围(0.008μg/mL-0.06μg/mL)选取16个孔并编号，各加入100μL MHB肉汤培养基。在第一孔中加入256μg/mL的美罗培南药液100μL，混合均匀后取100μL加入第2孔，如此倍比稀释至第14孔，最后弃去100μL，然后每孔接种已经稀释好的菌液100μL，得到美罗培南药液的浓度分别为：64μg/mL、32μg/mL、16μg/mL、8μg/mL、4μg/mL、2μg/mL、1μg/mL、0.5μg/mL、0.25μg/mL、0.125μg/mL、0.0625μg/mL、0.03125μg/mL、0.015625μg/mL、0.0078125μg/mL，第15孔不加美罗培南药液但接种菌液100μL，做为阳性对照，第16孔不加美罗培南药液也不加菌液，做为阴性对照。置恒温恒湿培养箱中37℃培养24h，观察结果。接种的菌液分质控菌和实验菌，并各做两次平行实验进行验证。
5.生长曲线的绘制
将冰箱里冷冻保存的配制好的中药提取物溶液和美罗培南取出，待融化至室温使用。在超净工作台中，将美罗培南稀释到使终浓度为对耐药菌MIC的1/4浓度，中药提取物溶液不稀释；再将琼脂板上已过夜培养好的细菌，挑单个菌落接种于营养肉汤培养基增殖，并将细菌稀释至1.5×106CFU/mL。
实验分为四个组：不加药组、美罗培南组、中药提取物组、中药提取物联合美罗培南组，在无菌的96孔聚丙烯微量滴定板中，不加药组加入肉汤100μL和细菌稀释液100μL；美罗培南组加入美罗培南药液和肉汤各50μL和细菌稀释液100μL；中药提取物组加入中药提取物溶液和肉汤各50μL和细菌稀释液100μL；中药提取物联合美罗培南组加入美罗培南药液和中药提取物溶液各50μL和细菌稀释液100μL。每组各设三个重复，实验区外围各孔滴加200μL肉汤封闭防止污染。置恒温恒湿培养箱中37℃培养24h，共在5个时间点(0h、1h、6h、12h、24h)测量各实验孔的OD值，波长为600nm，计算出各组每个时间点的平均值，然后根据数据绘制出细菌的生长曲线图，并计算抑菌率。
6.肉汤微量稀释棋盘法测定体外抗菌活性
根据生长曲线的结果，观察到中药提取物与美罗培南的联合抑菌率＞50％。重新配制浓度为32mg/mL的中药提取物溶液，将美罗培南稀释到使终浓度为对耐药菌MIC的2倍浓度，将配制好的中药提取物溶液和美罗培南药液在加样器中分别用肉汤倍比稀释7个浓度梯度。
在无菌的96孔聚丙烯微量滴定板中，每横排7个孔滴加美罗培南药液50μL，最后一孔不加药，从左至右各孔终浓度为：64μg/mL、32μg/mL、16μg/mL、8μg/mL、4μg/mL、2μg/mL、1μg/mL、0μg/mL；每竖排7个孔滴加中药提取物溶液50μL，最后一孔不加药，从上至下各孔终浓度为8mg/mL、4mg/mL、2mg/mL、1mg/mL、1/2mg/mL、1/4mg/mL、1/8mg/mL、0mg/mL。最后各孔滴加细菌稀释液100μL，放入恒温恒湿培养箱中培养18-24小时。第二天以肉眼观察无细菌生长的最低浓度为最小抑菌浓度(MIC)。分级抑菌浓度(FICI)指数值以确认受试中药提取物与美罗培南是否具有协同作用，FICI＝(MIC中药提取物联合/MIC中药提取物单用)+(MIC美罗培南联合/MIC美罗培南单用)。
判定标准为：当FICI≤0.5时，判定为两者具有协同作用；当0.5<FICI<4.0时，判定为两者具有无关作用；当FICI>4.0时，判定为两者具有拮抗作用。
7结果与分析
7.1美罗培南的MIC
观察培养24h后的细菌的生长情况，孔中培养基变得浑浊或有沉淀形成，表明有细菌生长，记为“+”，如培养基澄清透明见不到细菌，表明没有细菌生长，记为“-”。
质控菌的MIC结果见表1，美罗培南药物对质控菌的MIC为0.015625μg/mL，在其质控范围内。实验菌的MIC结果见表2，可见美罗培南对实验菌的MIC为32μg/mL。
表1质控菌的细菌生长结果
表2实验菌的细菌生长结果
7.2中药提取物联合美罗培南用药的生长曲线绘制
根据测得的OD值绘制出生长曲线图，测得两种中药提取物与美罗培南联合用药具有较好的抑菌作用(图1和图2)，抑菌率大于50％，其抑菌率结果见表3。
表3美罗培南与中药提取物联用的抑菌率
7.3肉汤微量稀释棋盘法结果观察
对中药提取物进行肉汤微量稀释棋盘实验，以进一步验证中药提取物与美罗培南药物的合作关系。将观察到的棋盘各孔细菌生长结果用表格表示，“-”代表无细菌生长，“+”代表有细菌生长。
黄芪多糖(65％)与美罗培南联用的细菌生长结果见表4，由表4可知：
黄芪多糖(65％)单用时的MIC为8mg/mL，联合时的MIC为1/2mg/mL；
美罗培南单用时的MIC为32μg/mL，联合时的MIC为1μg/mL；
所以FICI＝(1/2)/8+1/32，FICI<0.5，判定两者具有协同作用。
表4美罗培南与黄芪多糖(65％)联用的抗菌效果
芪贞增免颗粒与美罗培南联用的细菌生长结果见表5，由表5可知：
芪贞增免颗粒单用时的MIC为＞8mg/mL，联合时的MIC为4mg/mL；
美罗培南单用时的MIC为32μg/mL，联合时的MIC为1μg/mL；
所以FICI＝4/＞8+1/32，FICI<0.5，判定两者具有协同作用。
表5美罗培南与芪贞增免颗粒联用的抗菌效果
8.结论与讨论
本发明通过生长曲线绘制实验和肉汤微量稀释棋盘法实验，发现黄芪多糖或芪贞增免颗粒与美罗培南联合用药时具有协同作用，能够显著提高彼此对耐药菌的体外抑菌效果，且效果好于它们各自单独用药。
结合本实验结果表明，黄芪多糖或芪贞增免颗粒与美罗培南联合用药时，配比关系在一定范围内，具有很好的协同效果。本发明在探究中药提取物与抗生素联合用药时，通过大量实验研究了二者之间最优的配比关系，并得到了很好的抑菌配方。
本实验筛选出的黄芪多糖或芪贞增免颗粒能够联合美罗培南抑制其耐药菌的生长，这为进一步研究中西药联合对细菌的作用机制提供了方向，也对探究中草药提取物对其他耐药菌的体外抑菌作用有借鉴意义。
对比例
申请人在筛选中药提取物的过程中，将多种中药提取物与美罗培南联合后进行抑菌效果的比较，结果发现并不是每种组合都具有较好的抑菌效果或协同作用。在一些情况下，即使中药提取物本身具有抗菌作用，但与美罗培南联用后，并没有明显表现出较好的抑菌效果，也没有表现出联合用药后对美罗培南耐药菌的有效抑制作用或协同作用。
按本发明的实验方法同法操作，桑叶提取物、杜仲叶提取物、黄芩苷分别与美罗培南联合应用时，并没有表现出协同作用。它们的生长曲线图分别见图3-5，FICI均在0.5～4.0之间，这表明没有产生协同增效作用。
结论：
本发明在研究中药提取物与美罗培南联合用药时，意外地发现当黄芪多糖或芪贞增免颗粒在联合美罗培南用药时，对美罗培南耐药菌在体外有显著的抑制作用，且效果优于各自单独用药，因而美罗培南与所述黄芪多糖或芪贞增免颗粒联合用药时具有明显的协同作用。本发明的抗菌组合物中，黄芪多糖或芪贞增免颗粒与美罗培南抗生素联用具有增效和减毒优势。这样，每种物质在组合物中的相对用量会大大减少，进而减少可能的不良反应和副作用，提高用药安全性，同时还可以增加患者服用的依从性，从而保证疗效。
虽然，上文中已经用一般性说明、具体实施方式及试验，对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
Claims (2)
1.抗菌组合物，其特征在于，所述抗菌组合物由美罗培南和中药提取物组成，所述中药提取物为黄芪的提取物，所述黄芪的提取物为黄芪多糖，其总糖含量为65%，
其中，所述抗菌组合物由8μg/mL的美罗培南与1mg/mL的中药提取物组成；由4μg/mL的美罗培南与2mg/mL的中药提取物组成；由2μg/mL的美罗培南与2mg/mL的中药提取物组成；或，由1μg/mL的美罗培南与2mg/mL的中药提取物组成。
2.权利要求1所述的抗菌组合物在制备用于抗菌的药物中的用途，所述菌为美罗培南耐药菌，且所述美罗培南耐药菌为大肠杆菌。
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