CN114145299B - 一类具水杨酸结构骨架的衍生物在抗植物病原细菌和人源病菌中的应用 - Google Patents
一类具水杨酸结构骨架的衍生物在抗植物病原细菌和人源病菌中的应用 Download PDFInfo
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Abstract
本发明属于天然药物化学领域，公开了水杨酸衍生物及基于水杨酸片段而开发的商业化药剂在防治由水稻白叶枯病病原菌Xanthomonas oryzae ACCC 11602、柑橘溃疡病病原菌Xanthomonas axonopodis pv.Citri和马铃薯黑胫病病原菌Pectobacterium atroseptica ACCC 19901引起的植物病害和人源病菌大肠杆菌Escherichia coli ATCC 25922、金黄色葡萄球菌Staphyloccocus aureus sp.Newman和白色念珠菌Candida albicans ATCC 24433引起的疾病中的用途。以水杨酸片段而合成的衍生物及基于水杨酸片段而开发的商业化药剂具有易合成、成本低、杀菌广谱高效等特点，并且作为抗植物病原细菌剂在体内代谢为水杨酸激素后有诱导植物抗性的作用，具有进一步研究与开发的价值。化合物由以下通式表示：
Description
技术领域
本发明属于天然药物化学领域，公开了一类具水杨酸结构骨架的衍生物在防治由水稻白叶枯病病原菌Xanthomonas oryzae ACCC 11602、柑橘溃疡病病原菌Xanthomonasaxonopodis pv.Citri和马铃薯黑胫病病原菌Pectobacterium atroseptica ACCC 19901引起的农业细菌性病害和人源病菌大肠杆菌Escherichia coli ATCC 25922、金黄色葡萄球菌Staphyloccocus aureus sp.Newman和白色念珠菌Candida albicans ATCC 24433引起的疾病中的应用。
背景技术
水杨酸是存在于自然界的柳树皮、白珠树叶及甜桦树中的一种有机酸，作为一种重要有机合成原料，广泛应用于医药、农药、橡胶、染料、食品及香料工业。例如，水杨酸的乙酰化衍生物阿司匹林具有消炎镇痛、抗血栓、抗胆道蛔虫等药理作用，酰胺化衍生物氯硝柳胺广泛用于临床抗寄生虫病的治疗。
植物病原细菌是限制农业生产的主要原因之一，造成作物受害严重并引起巨大的经济损失。目前，对于植物细菌性病害的防治方法仍主要为化学防治，但由于化学药剂匮乏，且现有传统杀菌剂的长期使用和滥用导致植物病害抗药性增强。因此，急需探索和开发新型高效的杀菌剂作为替代性杀菌剂，以应对农药科学领域的问题。在大量筛选天然产物抗菌药物的过程中，我们发现水杨酸衍生物及基于水杨酸片段而开发的商业化药剂对水稻白叶枯病病原菌Xanthomonas oryzae ACCC 11602、柑橘溃疡病病原菌Xanthomonasaxonopodis pv.Citri、马铃薯黑胫病病原菌Pectobacterium atroseptica ACCC 19901均表现出一定的抑制作用。并且水杨酸作为一种植物激素，不仅能调节植物的一些生长发育过程，还可以诱导植物抗病性，可作为先导进一步开发。
多药耐药细菌病原体的日益出现和传播加速了对新抗菌药物的需求。大肠杆菌和金黄色葡萄球菌分别是临床感染中最常见的革兰阴性菌和革兰阳性菌之一，在一定条件下实现传播并引起人和多种动物发生胃肠道感染或尿道等多种局部组织器官感染。白色念珠菌是侵袭性念珠菌病的主要致病菌，当人体免疫力下降或病原菌侵入非正常寄居部位可引发严重感染。由于耐药性的发展，侵袭性真菌感染的死亡率居高不下，因此开发新型抗菌药物是一项至关重要的工作。在这里，我们也进一步测定了水杨酸衍生物及基于水杨酸片段而开发的商业化药剂对抗人源病菌大肠杆菌Escherichia coli ATCC 25922、金黄色葡萄球菌Staphyloccocus aureus sp.Newman和白色念珠菌Candida albicans ATCC 24433的潜力。
发明内容
本发明的目的是提供水杨酸衍生物及基于水杨酸片段而开发的商业化药剂类杀菌剂，用于防治由水稻白叶枯病病原菌、柑橘溃疡病病原菌、马铃薯黑胫病病原菌引起的植物病害和人源病菌大肠杆菌、金黄色葡萄球菌、白色念珠菌引起的疾病中的应用。
为实现上述目的，本发明提供了如下技术方法：
水杨酸衍生物及基于水杨酸片段而开发的商业化药剂共包括26种不同结构的化合物，测定以上化合物100μg/mL时对水稻白叶枯病病原菌Xanthomonas oryzae ACCC11602、柑橘溃疡病病原菌Xanthomonas axonopodis pv.Citri、马铃薯黑胫病病原菌Pectobacterium atroseptica ACCC 19901、大肠杆菌Escherichia coli ATCC 25922、金黄色葡萄球菌Staphyloccocus aureus sp.Newman和白色念珠菌Candida albicans ATCC24433的抑制率。对于抑制率大于90％的化合物，通过二倍稀释法进行了低浓度活性测定。
本发明提供的水杨酸衍生物作为新型杀菌剂，具有以下优势：
1)水杨酸作为植物激素可以诱导植物抗病性，其衍生物及基于水杨酸片段而开发的商业化药剂为抗植物病原细菌剂除了对细菌的直接抑制作用，还有望于在植物体内被吸收代谢后诱导抗性。
2)杀菌活性高。部分化合物在低于1μg/mL的给药浓度时，抑制率仍在90％以上，可作为杀菌先导进行生物合理性设计与开发。
3)利用“老药新用”策略发现了部分目前基于水杨酸片段而开发的商业化药剂的抗菌新用途。对于已上市药物进行新适应症的开发，大大降低了药物的研发成本与周期。
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。下列实施例中所述实验方法，如无特殊说明，均为常规方法。
实施例1：水杨酸衍生物及基于水杨酸片段而开发的商业化药剂，包含了26种不同结构的化合物。其结构式如下：
实施例2：水杨酸衍生物及基于水杨酸片段而开发的商业化药剂抗菌活性测定
本实验中所用的菌株为实验室-80℃含30％甘油冻存的菌株。将冻存菌株取出，分别在植物细菌的NB固体培养基(牛肉膏：3g，蛋白胨：5g，酵母粉：1g，蔗糖：10g，琼脂：15g，蒸馏水：1L，pH7.0；121℃灭菌20min)、人源细菌的NB固体培养基(牛肉膏：3g，蛋白胨：10g，氯化钠：5g，琼脂：15g，蒸馏水：1L，pH7.0；121℃灭菌20min)和念珠菌的YEPD固体培养基(酵母膏：10g，蛋白胨：20g，葡萄糖：20g，琼脂：15g，蒸馏水：1L；121℃灭菌20min)上面进行划线，在28℃(37℃)下恒温培养直到长出单菌落。分别挑取固体培养基上单菌落至植物细菌NB液体培养基(牛肉膏：3g，蛋白胨：5g，酵母粉：1g，蔗糖：10g，蒸馏水：1L；121℃灭菌20min)、人源细菌NB液体培养基(牛肉膏：3g，蛋白胨：10g，氯化钠：5g，蒸馏水：1L，pH7.0；121℃灭菌20min)和念珠菌的YEPD液体培养基(酵母膏：10g，蛋白胨：20g，葡萄糖：20g，蒸馏水：1L；121℃灭菌20min)中，在28℃(37℃)、180rpm恒温摇床振荡培养到对数生长期。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，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，最终给药浓度为100μg/mL。含等量DMSO的相同浓度100μL菌液做对照。将96孔板在28℃(37℃)恒温培养箱中培养24-48h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.水杨酸衍生物100μg/mL下的抗菌活性
注：“-”表示化合物的抗菌活性未测定
由表1生测结果可知，本发明涉及的水杨酸衍生物对测定菌株均表现出一定的抗菌活性，其中对水稻白叶枯病病原菌表现出高活性的化合物最多。
实施例3：高活性水杨酸衍生物及基于水杨酸片段而开发的商业化药剂最低抑菌浓度(MIC)测定
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2中相同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.高活性化合物的MIC值
注：“a”表示化合物的MIC值大于800μg/mL，“/”表示化合物的MIC值大于100μg/mL，“-”表示化合物的抗菌活性未测定
由表2生测结果可知，部分水杨酸衍生物对测定菌株均表现出良好的抗菌活性，其中对水稻白叶枯病病原菌、柑橘溃疡病病原菌、金黄色葡萄球菌的作用最强，MIC值最小可达0.10μg/mL，对马铃薯黑胫病病原菌、大肠杆菌、白色念珠菌表现出较弱的抑制作用。
综上所述，本发明所述的水杨酸衍生物对植物病原细菌和人源病菌均表现出一定的抑制作用，并且活性较水杨酸均有所提高，其中部分已上市药物发现了抗菌作用的新用途，具有进一步研究和开发的价值。
Claims (1)
1.氯羟柳胺在抗植物病原细菌方面的用途，所述植物病原细菌为水稻白叶枯病菌，柑橘溃疡病菌和马铃薯黑胫病菌。
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