CN117797197A - 博落回总生物碱及主要成分异喹啉类生物碱在抑制奶牛乳腺炎致病菌中的应用 - Google Patents
博落回总生物碱及主要成分异喹啉类生物碱在抑制奶牛乳腺炎致病菌中的应用 Download PDFInfo
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Abstract
本发明公开了博落回总生物碱及其主要异喹啉类生物碱——血根碱及白屈菜红碱新的活性及应用，属于天然药物化学领域。抑菌活性研究表明，博落回总生物碱及其主要成分血根碱及白屈菜红碱对奶牛乳腺炎致病菌无乳链球菌Streptococcus agalactiae ATCC12386，无乳链球菌Streptococcus agalactiae ATCC27956，停乳链球菌Streptococcus dysgalactiae ATCC27957及金黄色葡萄球菌Staphylococcus aureus Newman均表现出优异的抑制活性，其中白屈菜红碱活性最好，MIC90值为6.25μg/mL，其抑菌活性与阳性对照药品诺氟沙星相比相当或更加优异，因此在治疗奶牛乳腺炎方面极具开发价值。
Description
技术领域
本发明属于天然药物化学领域，公开了一种博落回总生物碱及其主要异喹啉类生物碱——血根碱、白屈菜红碱新的活性和用途，具体涉及其在抑制奶牛乳腺炎致病菌——无乳链球菌Streptococcus agalactiaeATCC12386，无乳链球菌Streptococcus agalactiaeATCC27956，停乳链球菌Streptococcus dysgalactiaeATCC27957和金黄色葡萄球菌Staphylococcus aureusNewman中的应用。
背景技术
奶牛乳腺炎作为奶牛养殖业最常见的疾病之一，可引起发病奶牛泌乳量减少，影响牛乳品质和营养成分的含量，甚至导致奶牛生产性能丧失，使成年奶牛过早淘汰。导致奶牛乳腺炎发生的因素很多，包括物理性刺激、化学物质侵染以及病原微生物的入侵，然而近50%的奶牛乳腺炎是由细菌感染引起的。奶牛乳腺炎给全世界的奶牛养殖产业和乳制品加工业造成了巨大的经济损失，也是影响奶牛健康和乳制品安全的关键因素。此外，由此带来的食品安全问题严重威胁着人类健康。目前，抗生素的应用仍是防治奶牛乳腺炎的主要策略。然而，反复及不当使用抗生素可诱导菌株对抗生素产生耐药性，严重影响其疗效。同时，抗生素残留的发生不仅造成奶牛肠道菌群失调，导致牛乳中蓄积药物，严重威胁人们日常饮食安全，还会对水和土壤环境造成负面影响，进而危害人们的生活环境。因此，乳腺炎病原体的抗生素耐药性已成为全球广泛关注的问题，迫使人们开发安全有效的“替抗”活性化合物以维持奶牛乳房的健康。
植物资源是丰富的活性天然产物库，其产生的次生代谢产物超过400,000种，且其中多数都具有良好的抗菌活性，因而天然产物一直是药物研发的重要来源。在过去的二十几年中，超过1/3的FDA批准上市药物为天然产物及其衍生物。相比于化学合成的化合物，天然产物具有一些独特的性质，例如：结构复杂度更高、骨架更加新颖、类药性更好等。因此，天然产物是一个值得关注的资源宝库，在新药开发中具有巨大潜力。博落回（Macleaya cordata(Willd. ) R. Br.）是罂粟科博落回属多年生高大草本，在我国分布广泛、资源丰富。博落回全属共两种，即博落回和小果博落回（Macleaya microcarpa(Maxim) Fedde）。博落回总生物碱中含多种化学成分，其主要的生物活性物质为异喹啉类生物碱，例如血根碱、白屈菜红碱、原阿片碱、别隐品碱等。近代药理研究表明，血根碱对6株水产病原菌都有不同程度的抑制作用，其中对嗜水气单胞菌嗜水亚种的活性最强，其MIC和MBC分别为12．5mg/L和25mg/L。对哈维弧菌、鳗弧菌、杀鲑气单胞菌史氏亚种的活性最弱，其MIC和MBC分别为50mg/L和100mg/L。郁建平等研究表明，盐酸血根碱对木霉、青霉、根霉、黄曲霉、黑曲霉、米曲霉、毛霉、酵母均具有很强的抗菌作用，且盐酸血根碱对8种真菌的最低抑菌浓度都很低，其中青霉、毛霉的最低抗菌浓度为80g/mL，木霉、根霉、黄曲霉、黑曲霉、米曲霉和酵母最低抗菌浓度均小于40ug/mL，作为植物源天然抗菌剂，其抗菌谱宽，效果十分明显。白屈菜红碱具有显著的抗肿瘤活性，对某些真菌、细菌和病毒有抑制作用，但对神经、心脏等有毒害，可引起麻痹、心脏抑制，甚至导致死亡。在体外可抑制甲型链球菌、卡他、I型奈氏菌、粘膜奈氏菌、肺炎双球菌、流感嗜血杆菌和其他革兰氏阳性细菌。在体内可抑制结核杆菌。低浓度的白屈菜红碱能抑制噬菌体和大肠杆菌。目前，关于异喹啉类生物碱对奶牛乳腺炎主要致病菌的抑制作用尚未见报道。
发明内容
本发明的目的是对博落回总生物碱及其主要成分异喹啉类生物碱——血根碱、白屈菜红碱的主要致病菌的抑制作用进行研究，以期用于防治由乳链球菌、无乳链球菌、停乳链球菌引起的奶牛乳腺炎。
本发明涉及的异喹啉类生物碱为血根碱、白屈菜红碱，二者的结构式如下：
。
下面通过具体实验测定异喹啉类生物碱对奶牛乳腺炎致病菌乳链球菌Streptococcus agalactiaeATCC12386，无乳链球菌Streptococcus agalactiaeATCC27956，停乳链球菌Streptococcus dysgalactiaeATCC27957的抑菌活性。
1. 供试药剂
博落回总生物碱、血根碱及白屈菜红碱。
2.供试菌种
无乳链球菌Streptococcus agalactiaeATCC12386，无乳链球菌Streptococcus agalactiaeATCC27956，停乳链球菌Streptococcus dysgalactiaeATCC27957和金黄色葡萄球菌Staphylococcus aureusNewman。
3. 测试方法
本实验所用的菌株为实验室-80℃含30 %甘油冻存的菌株。将无乳链球菌和停乳链球菌冻存菌株取出，分别在TSA（胰酪大豆胨琼脂培养基）+5%羊血琼脂平板上面进行划线，在37℃下恒温培养直到长出单菌落。分别挑取单菌落至脑心浸出液肉汤（BHI）液体培养基（胰蛋白胨：10.0 g，牛心浸粉：17.5 g，氯化钠：5.0 g，葡萄糖：2.0 g，磷酸氢二钠（12H2O）：2.5 g，蒸馏水：1 L；121℃灭菌20 min），在37℃、140 rpm恒温摇床振荡培养到对数生长期。同样的，将大肠杆菌和金黄色葡萄球菌的冻存菌株取出，分别在MH固体培养基（牛肉粉：2.0 g，可溶性淀粉：1.5 g，酸水解酪蛋白：17.5 g，琼脂：20 g，蒸馏水：1 L；121℃灭菌20 min）上面进行划线，在37℃下恒温培养直到长出单菌落。分别挑取单菌落至MH肉汤培养基（牛肉粉：2.0 g，可溶性淀粉：1.5 g，酸水解酪蛋白：17.5 g，蒸馏水：1 L；121℃灭菌20 min）液体培养基。然后，分别将处于对数生长期的菌株用相应的液体培养基稀释至约106 CFU/mL备用。将化合物分别用DMSO溶解，加入液体培养基中，混合均匀，将博落回总生物碱、血根碱及白屈菜红碱配制成浓度为200 μg/mL的含药液体培养基。取50 μL含药培养基和相同体积的含约106 CFU/mL细菌培养物加入到96孔板的孔中，最终博落回提取物、血根碱及白屈菜红碱都为100 μg/mL。含等量DMSO的相同浓度100 μL菌液做对照。
将96孔板在37℃恒温培养箱中培养12~24 h直至对照组菌液长出，在酶标仪上测定孔中菌液的OD值（OD600）。并且另外测定100 μL液体培养基和浓度为100 μg/mL药剂的OD值，对培养基和药剂本身造成的OD值进行矫正。校正OD值和抑制率的计算公式如下：
校正OD值 = 含菌培养基OD值 - 无菌培养物OD值；
抑制率 = (校正后对照培养基菌液OD值-校正后含药培养基OD值)/校正后对照培养基菌液OD值×100%
所有实验设置三个重复，测定得到化合物的抑制率见表1。由表1所测结果可知，本发明涉及的博落回总生物碱、血根碱及白屈菜红碱对所测定菌株均表现出优异的抗菌活性。
将博落回总生物碱、血根碱及白屈菜红碱的含药液体培养基在96孔板中通过二倍稀释法稀释得到系列浓度的50 μL含药培养基，然后根据上述试验方法测定系列浓度对应的抑制率。将抑制率大于90%的最低浓度定义为MIC90，测定得到的活性数据见表2。
由表2的实验结果可知，本发明涉及的博落回总生物碱、血根碱及白屈菜红碱对无乳链球菌Streptococcus agalactiaeATCC12386，无乳链球菌Streptococcus agalactiaeATCC27956，停乳链球菌Streptococcus dysgalactiaeATCC27957均表现出优异的抗菌活性，其中白屈菜红碱活性最好，其对无乳链球菌Streptococcus agalactiaeATCC12386，无乳链球菌Streptococcus agalactiaeATCC27956，停乳链球菌Streptococcus dysgalactiaeATCC27957的MIC90值均为6.25 μg/mL，抑菌活性与阳性对照药品诺氟沙星相比相当或更加优异。同时，博落回中总生物碱、血根碱、白屈菜红碱对金黄色葡萄球菌 Newman的MIC90值分别为100，50，3.12μg/mL，而阳性对照药品诺氟沙星则无抗金黄色葡萄球菌 Newman活性，因此博落回中总生物碱、血根碱、白屈菜红碱在治疗奶牛乳腺炎方面极具开发价值。
Claims (3)
1.博落回总生物碱及主要成分异喹啉类生物碱在抑制奶牛乳腺炎致病菌中的应用。
2.如权利要求1所述博落回总生物碱及主要成分异喹啉类生物碱在抑制奶牛乳腺炎致病菌中的应用，其特征在于：所述异喹啉类生物碱为血根碱、白屈菜红碱。
3.如权利要求1或2所述博落回总生物碱及主要成分异喹啉类生物碱在抑制奶牛乳腺炎致病菌中的应用，其特征在于：所述奶牛乳腺炎致病菌为无乳链球菌Streptococcus agalactiae ATCC12386、无乳链球菌Streptococcus agalactiae ATCC27956、停乳链球菌Streptococcus dysgalactiae ATCC27957、金黄色葡萄球菌Staphylococcus aureus Newman。
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