CN117618428A - 一种白叶藤碱类生物碱在防治奶牛乳腺炎致病菌中的用途 - Google Patents
一种白叶藤碱类生物碱在防治奶牛乳腺炎致病菌中的用途 Download PDFInfo
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Abstract
本发明公开白叶藤碱类生物碱，包括白叶藤碱、新白叶藤碱、异白叶藤碱和异新白叶藤碱在防治奶牛乳腺炎致病菌方面的用途，属于天然药物化学领域。四种白叶藤碱类生物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，大肠杆菌Escherichia coli ATCC 25922和金黄色葡萄球菌Staphylococcus aureus Newman表现出优异的抑制活性，在代替抗生素成为防治奶牛乳腺炎天然产物来源化合物方面极具开发价值。本专利所涉及的化合物结构式如下：
Description
技术领域
本发明属于天然药物化学领域，公开了一种白叶藤碱类生物碱，包括白叶藤碱、新白叶藤碱、异白叶藤碱和异新白叶藤碱的新用途，具体涉及其在防治由无乳链球菌Streptococcus agalactiae ATCC12386，无乳链球菌Streptococcus agalactiaeATCC27956，停乳链球菌Streptococcus dysgalactiae ATCC27957，大肠杆菌Escherichiacoli ATCC 25922和金黄色葡萄球菌Staphylococcus aureus Newman致病菌引起的奶牛乳腺炎中的用途。
背景技术
奶业是畜牧业最重要的经济产业之一，乳腺炎是奶牛生产中最常发生的疾病，奶牛乳腺炎的发生严重影响奶牛生产中的乳品质和乳产量。造成乳腺炎的原因有病原体感染、环境管理和奶牛个体原因等，通常以病原体感染为最易发病诱因，持续长期的炎症反应会使乳腺小叶受到损伤、炎性细胞浸润、乳腺上皮细胞增生和乳腺淋巴结肿大，情况严重时会导致乳腺组织坏死和萎缩，直至泌乳功能丧失。同时，乳汁中会出现絮状沉淀和异味，并伴随着乳汁中体细胞含量增多，导致奶牛产奶量降低、乳品质变差和治疗成本提升，甚至过早淘汰母牛，造成巨大的经济损失。
目前，通常治疗奶牛乳腺炎的有效手段是使用抗生素，但由于近年抗生素的过度使用，导致牛奶中抗生素含量远远超过正常标准，也严重威胁着人类健康安全，并且许多种类抗生素的使用导致病原菌产生了高强度的耐药性，细菌耐药性问题在高产奶牛乳腺炎中尤其突出。不断出现的耐药菌株，使抗生素的治疗效果逐渐降低。对于当前形势下致病菌耐药性的大幅度提升，从根源上阻止致病菌产生耐药性的重要性在奶牛养殖过程中突显出来，使用天然无害的抗生素替代物成为了研究的热点和公众关注的热点之一。
白叶藤碱(cryptolepine)、新白叶藤碱(new cryptolepine)和异白叶藤碱(isocryptolepine)是从非洲传统药材血红白叶藤中提取的具有独特吲哚并喹啉结构的天然生物碱，目前关于该类生物碱及其衍生物的生物活性报道主要集中于抗疟、抗高血糖、抗肿瘤、抗炎等方面，本课题组针对白叶藤碱类生物碱在抗细菌真菌方面的应用领域进行长期持续深入全面的研究，研发了一系列具有优异活性的化合物，包括白叶藤碱、新白叶藤碱、异白叶藤碱和异新白叶藤碱，而关于这类生物碱及其衍生物在防治奶牛乳腺炎致病菌上尚未见报道。本发明选取重要的奶牛乳腺炎致病细菌为研究对象，结果证明白叶藤碱类生物碱具有优异的抗菌效果，在治疗奶牛乳腺炎方面具有潜在的开发价值。
发明内容
本发明的目的是提供白叶藤碱类生物碱在治疗奶牛乳腺炎方面的新用途，用于防治由无乳链球菌、停乳链球菌、大肠杆菌和金黄色葡萄球菌致病菌引起的奶牛乳腺炎。
为了实现以上目的，本发明提供了如下技术方法：
本发明提供了一种白叶藤碱类生物碱包括白叶藤碱、新白叶藤碱、异白叶藤碱和异新白叶藤碱，在抗奶牛乳腺炎致病细菌中的新用途，其对无乳链球菌Streptococcusagalactiae ATCC12386，无乳链球菌Streptococcus agalactiae ATCC27956，停乳链球菌Streptococcus dysgalactiae ATCC27957，大肠杆菌Escherichia coli ATCC 25922和金黄色葡萄球菌Staphylococcus aureus Newman的给药浓度为100、50、25、12.5、6.25、3.12μg/mL等。本发明涉及的化学结构式如下：
本发明提供的抗菌剂，尤其是异白叶藤碱和异新白叶藤碱对奶牛乳腺炎致病菌表现出优异的抑制作用，在治疗奶牛乳腺炎方面极具开发价值。而且，天然源抗菌剂因其具有低毒、低残留及不易产生抗性等优点，在防治奶牛乳腺炎方面具有无法替代的独特性，值得进一步研究和开发。
具体实施方式
为了更好地理解本发明，通过以下具体实施例对本发明的上述内容做进一步的详细说明。但不应将此理解为对本发明的限制。以下是本发明的具体实施例，对本发明的技术方案做进一步描述，但本发明的内容不仅仅局限于实施例所述的范围，凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
实施例1：白叶藤碱类生物碱抗奶牛乳腺炎致病菌活性测定
1)供试药剂：白叶藤碱、新白叶藤碱、异白叶藤碱和异新白叶藤碱。
2)供试菌种：无乳链球菌Streptococcus agalactiae ATCC12386，无乳链球菌Streptococcus agalactiae ATCC27956，停乳链球菌Streptococcus dysgalactiaeATCC27957，大肠杆菌Escherichia coli ATCC 25922和金黄色葡萄球菌Staphylococcusaureus Newman。
3)测试方法：
本实验中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：10.0g，牛心浸粉：17.5g，氯化钠：5.0g，葡萄糖：2.0g，磷酸氢二钠(12H2O)：2.5g，蒸馏水：1L；121℃灭菌20min)，在37℃、140rpm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：2.0g，可溶性淀粉：1.5g，酸水解酪蛋白：17.5g，琼脂：20g，蒸馏水：1L；121℃灭菌20min)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：2.0g，可溶性淀粉：1.5g，酸水解酪蛋白：17.5g，蒸馏水：1L；121℃灭菌20min)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106CFU/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，将白叶藤碱、新白叶藤碱、异白叶藤碱和异新白叶藤碱配制成浓度为200μg/mL的含药液体培养基。取50μL含药培养基和相同体积的含约106CFU/mL细菌培养物加入到96孔板的孔中，最终化合物浓度都为100μg/mL。含等量DMSO的相同浓度100μL菌液做对照。将96孔板在37℃恒温培养箱中培养12-24h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100μL液体培养基和浓度为100μg/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。
表1.白叶藤碱类生物碱在100μg/mL对奶牛乳腺炎致病细菌的抑制率(％)
由表1所测结果可知，本发明涉及的白叶藤碱类生物碱对测定菌株均表现出优异的抗菌活性。
将活性化合物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50μL含药培养基，然后根据实施例1中的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MIC，测定得到的活性数据见表2。
表2.白叶藤碱类生物碱抗奶牛乳腺炎致病细菌的MIC值
由实验结果可知，本发明涉及的白叶藤碱类生物碱对测试菌株均表现出优异的杀菌活性，其中异白叶藤碱具有广谱抗菌活性且活性最好，MIC值在6.25～25μg/mL，表现出显著的抗菌活性。
综上所述，本发明所述的白叶藤碱类生物碱包括白叶藤碱、新白叶藤碱、异白叶藤碱和异新白叶藤碱对无乳链球菌Streptococcus agalactiae ATCC12386，无乳链球菌Streptococcus agalactiae ATCC27956，停乳链球菌Streptococcus dysgalactiaeATCC27957，大肠杆菌ATCC 25922，金黄色葡萄球菌Newman表现出显著的抗菌活性，可在防治奶牛乳腺炎方面进一步研究和开发。
Claims (3)
1.本发明涉及白叶藤碱类生物碱，包括白叶藤碱、新白叶藤碱、异白叶藤碱和异新白叶藤碱在防治奶牛乳腺炎中的应用。
2.根据权利要求1所述的用途，其中，所涉及化合物结构式如下：
3.根据权利要求1-2所述的涉及白叶藤碱类生物碱，包括白叶藤碱、新白叶藤碱、异白叶藤碱和异新白叶藤碱在防治由无乳链球菌Streptococcus agalactiae ATCC12386，无乳链球菌Streptococcus agalactiae ATCC27956，停乳链球菌Streptococcus dysgalactiaeATCC27957引起的奶牛乳腺炎中的用途。
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