CN111166749A - 血根碱在抑制肺炎链球菌生长中的应用 - Google Patents
血根碱在抑制肺炎链球菌生长中的应用 Download PDFInfo
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Abstract
本发明公开了血根碱在抑制肺炎链球菌生长中的应用，根据血根碱对肺炎链球菌具有较好的体外杀灭作用，能够抑制肺炎链球菌的生长，且最低杀菌浓度为31.2μg/mL，最小抑菌浓度为15.6μg/mL，本发明提出了血根碱对肺炎链球菌具有抑制作用，在医药等领域具有广泛的应用价值。
Description
技术领域
本发明涉及医药、食品安全领域，具体涉及血根碱在抑制肺炎链球菌生长中的应用。
背景技术
肺炎链球菌(Streptococcus pneumoniae)是一种链球菌科链球菌属革兰氏阳性细菌，是儿童发生社区获得性肺炎的主要致病菌，肺炎链球菌感染就是因为体内肺炎链球菌的入侵导致的，主要病症包括肺炎、脑膜炎、中耳炎等。正常情况下肺炎链球菌往往处于带菌状态，主要在人体鼻咽部上皮细胞、口腔上皮细胞内附着，但是一旦身体免疫功能下降，或者受到生理侵犯、机械屏障损伤等，会为肺炎链球菌繁殖提供更多的机会，进而会蔓延到鼻腔、支气管、中耳、肺部等，从而导致器官发生炎性反应，严重时引发全身感染，严重威胁生命健康。研究显示，肺炎链球菌主要引起人类大叶性肺炎。75％的成年人肺炎链球菌肺炎及50％以上严重的肺炎链球菌菌血症是由1～8型肺炎链球菌引起。肺炎链球菌6、14、19及23型常引起儿童肺炎链球菌性疾病。40％～70％的正常人上呼吸道中携带有毒力的肺炎链球菌。据文献报道的肺炎链球菌感染的年龄分布，年龄小于两岁例感染数所占比例为62％，发病季节主要集中在冬季，发病率为56％，主要疾病为肺炎。肺炎链球菌对剃奈唑胺、厄他培南、万古霉素、莫西沙星敏感率都为100％，对红霉素耐药率为98％，但肺炎链球菌对抗生素日益上升的耐药性给医院的治疗工作带来了极大的影响。
血根碱是一种苯菲啶异喹啉类生物碱，主要存在于白屈菜的全草、紫堇的块根、博落回的全草、血水草的地上部分，由二氢苯并啡啶氧化酶氧化二氢血根碱而成。临床研究结果表明，血根碱对口腔中大多数细菌有抑菌和杀菌作用，并有干扰细菌粘附于刚形成的牙膜上的作用。血根碱对一些真菌，如毛癣菌菌株、犬小孢子菌、絮状麦皮癣菌和烟曲霉菌等均具有抑制作用。血根碱还具有抗氧化以及抗炎症的作用，也用来控制血吸虫，此外还具有抗肿瘤特性。据报道，血根碱对于胰腺癌有治疗作用。试验证明，血根碱能显著抑制胰腺癌细胞AsPC-l和BxPC-3的生长、发育，及其菌落的形成能力。Haseeb Ahsan(2007)也证实，血根碱可以通过调节Bcl-2蛋白的途径达到诱导人胰腺癌细胞AsPC-1和BxPC-3的凋亡。中国专利CN110772518A公开了血根碱在抑制路邓葡萄球菌生长中的应用，但是目前没有血根碱抑制高致病性肺炎链球菌生长方面的文献报道。
发明内容
本发明针对目前临床医学和食品安全中面临的耐药难题，目的在于提供血根碱在抑制肺炎链球菌生长中的应用。
为了实现上述目的，本发明采用的技术方案为：
利用微量二倍稀释法确定肺炎链球菌对抗生素的耐药性，然后确定了血根碱对肺炎链球菌的最小抑菌浓度(MIC)和最低杀菌浓度(MBC)。结果表明：血根碱对肺炎链球菌具有较好的抑菌作用，可以用于抑制肺炎链球菌的生长。
优选的，所述肺炎链球菌为耐氧氟沙星、四环素、复方新诺明中多种抗生素的人源肺炎链球菌。
优选的，所述肺炎链球菌选自耐氧氟沙星、四环素及复方新诺明的人源肺炎链球菌。
优选的，所述血根碱的最低杀菌浓度为31.2μg/mL，最小抑菌浓度为15.6μg/mL。
本发明的有益效果体现在：
本发明从现存的药用植物资源库入手，挖掘潜在的耐药菌抑制剂，基于血根碱对肺炎链球菌的作用的研究，发现非抗生素类化合物血根碱可以有效抑制肺炎链球菌的生长，为肺炎链球菌抑制剂的研究开发和应用提供新的思路和来源，在医药等领域具有广泛的应用价值。
进一步的，本发明明确了血根碱对肺炎链球菌的抑制作用，将其作为抗生素替代品，可有效缓解或解决肺炎链球菌的耐药及感染问题，降低病死率。
具体实施方式
下面结合实施例对本发明做进一步详细说明。所述实施例仅用于解释本发明，并非对本发明保护范围的限制。
1、肺炎链球菌的药敏实验
本发明以多株人源肺炎链球菌(菌株样本取自北京市海淀医院)为出发菌株，选用左旋氧氟沙星、氧氟沙星、莫西沙星、红霉素、氯霉素、泰利霉素、四环素、万古霉素、利奈唑胺、复方新诺明10种常用抗生素进行试验。
挑取培养18～24h的纯菌落均匀溶解于2～5mL无菌生理盐水中，调节其浊度与0.5麦氏比浊管等浊。利用试管二倍稀释法将抗生素、菌液及TSB液体培养基加入96孔培养板中过夜培养，不同浓度的药液组别均为三个平行，确保实验数据的可信度。利用酶标仪测定血根碱对肺炎链球菌的最小抑菌浓度。抑菌结果根据美国临床试验室国家标准化管理委员会(CLSl2017)标准判定，判定标准见表1，实验结果见表2。由此可知，2#菌株耐药性较强(1#菌株分型为2型，2#菌株分型为6型)。
表1.美国临床试验室国家标准化管理委员会(CLSl2017)标准判定结果
表2.人源肺炎链球菌的药敏试验MIC结果
2、血根碱对多重耐药菌株的抑制作用
为了充分考虑用药安全，本发明以血根碱这一单一活性成分为研究对象，以标准菌株(ATCC-49619，对阿莫西林、美洛培南、厄他培南、左旋氧氟沙星、氧氟沙星、莫西沙星、红霉素等抗生素敏感)作为参考，进行抑制作用的研究。挑取培养24h的纯菌落均匀溶解于5mL TSB液体培养基中，调节其浊度与0.5麦氏比浊管等浊，并用酶标仪测定其OD600值。用二甲基亚砜配制浓度为1000μg/mL的血根碱作为药液，利用试管二倍稀释法将药液、菌液及TSB液体培养基加入96孔培养板中过夜培养，不同浓度的药液组别均为三个平行，确保实验数据的可信度。
利用酶标仪测定血根碱对肺炎链球菌的最小抑菌浓度(MIC)，并以MIC浓度为参照，对进行培养的菌液增加药物稀释梯度，将相应培养液转接于无菌的TSA固体培养基中培养24h，若无单菌落生成，则对应浓度为血根碱对肺炎链球菌的最低杀菌浓度(MBC)，实验结果见表3。
表3.血根碱对肺炎链球菌的抑制结果
由表3可知，血根碱对耐氧氟沙星、四环素及复方新诺明的肺炎链球菌的抑制作用较好，其MIC为15.6μg/mL，MBC为31.2μg/mL。结果表明血根碱不仅对肺炎链球菌参考菌株有抑菌作用，对本发明中的肺炎链球菌(例如，2#菌株)也有抑菌作用。
根据以上实验结果，结合中草药来源广泛、不良反应少及不易产生耐药性等特点，可通过获得活性单品成分血根碱，直接针对临床主要的肺炎链球菌发挥抑制作用，能够有效缓解或解决肺炎链球菌的感染问题，降低病死率，为研究临床分离的肺炎链球菌的抑菌剂提供科学依据，为开发抑制肺炎链球菌的药物和抗生素替代品提供新思路和来源。
Claims (10)
1.血根碱在抑制肺炎链球菌生长中的应用。
2.根据权利要求1所述的应用，其特征在于：所述肺炎链球菌为人源肺炎链球菌。
3.根据权利要求1所述的应用，其特征在于：所述肺炎链球菌的耐药性是通过微量二倍稀释法确定的。
4.根据权利要求1所述的应用，其特征在于：所述肺炎链球菌耐受的抗生素选自氧氟沙星、四环素、复方新诺明中的多种。
5.根据权利要求1所述的应用，其特征在于：所述肺炎链球菌选自耐氧氟沙星、四环素及复方新诺明的肺炎链球菌。
6.根据权利要求5所述的应用，其特征在于：所述血根碱对肺炎链球菌的最低杀菌浓度为31.2μg/mL，最小抑菌浓度为15.6μg/mL。
7.根据权利要求1所述的应用，其特征在于：所述血根碱对肺炎链球菌具有体外杀灭作用，以及抑制肺炎链球菌的体外生长。
8.血根碱在制备抗肺炎链球菌的药物中的应用。
9.根据权利要求8所述的应用，其特征在于：所述肺炎链球菌为人源肺炎链球菌。
10.根据权利要求8所述的应用，其特征在于：所述肺炎链球菌选自对氧氟沙星、四环素、复方新诺明中多种抗生素耐药的肺炎链球菌。
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