CN110123801A - 一种多臂aie分子在制备抗菌药物中的用途和抗菌药物 - Google Patents

一种多臂aie分子在制备抗菌药物中的用途和抗菌药物 Download PDF

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CN110123801A
CN110123801A CN201910506432.2A CN201910506432A CN110123801A CN 110123801 A CN110123801 A CN 110123801A CN 201910506432 A CN201910506432 A CN 201910506432A CN 110123801 A CN110123801 A CN 110123801A
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arm
molecule
antibacterials
aie
aie molecule
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CN110123801B (zh
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蒋兴宇
贾跃晓
唐荣冰
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Southwest University of Science and Technology
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Southwest University of Science and Technology
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Abstract

本发明提供了一种多臂AIE分子在制备抗菌药物中的用途和抗菌药物。所述多臂AIE分子是指具有一个核心结构和与所述核心结构相连的至少2个共轭刚性臂结构的多臂AIE分子。所述抗菌药物包括至少一种上述多臂AIE分子和分散介质。本发明研究发现，具有多个共轭刚性臂结构的AIE分子可以将其共轭刚性臂结构插入细菌的细胞壁中，通过阻碍转糖和转肽过程来影响细菌细胞壁合成，从而抑制或杀灭细菌。由该多臂AIE分子制备的抗菌药物具有广谱的抗菌功能，能够有效抑制细菌生长，杀死高浓度细菌，并且可以清除成熟生物膜中的细菌，治疗多药耐药细菌引起的体内感染。

Description

一种多臂AIE分子在制备抗菌药物中的用途和抗菌药物
技术领域
本发明属于抗菌技术领域，具体涉及一种多臂AIE分子在制备抗菌药物中的用途和抗菌药物。
背景技术
致病菌是引发院内感染和社区感染的重要因素，会引起多种疾病，如皮肤与软组织感染、骨髓炎、心内膜炎、肺炎、菌血症，甚至败血症。现有的治疗细菌感染的药物包括β-内酰胺类、大环内脂类、四环素类、多肽类和喹诺酮类等。但是随着这些药物广泛使用，细菌出现了严重的耐药性，威胁着临床的抗感染治疗。因此寻找和开发新的抗菌药物是解决细菌耐药性，保证人类身体健康的一个迫切和重要的需求。
目前人们开发新的抗菌药物主要通过以下几种方法：(1)筛选天然抗菌分子；(2)合成传统抗生素的衍生物；(3)合成抗菌聚合物；(4)合成抗菌纳米颗粒。
其中，天然的抗菌物质已经被人们充分探索，因此筛选天然抗菌物质速率慢，产率低；抗生素的衍生物是根据传统抗生素结构设计合成的，它们与传统抗生素的抗菌机制相同或者相似，因此容易出现交叉耐药现象；抗菌聚合物毒性大，溶解性差，无法直接用于感染类疾病的体内治疗；抗菌纳米颗粒的稳定性、毒性以及体内药物代谢还有待进一步研究。
CN 104224776A公开了一种四苯乙烯衍生物在制备抗菌药物中的用途，CN104224775A公开了一种包含四苯乙烯衍生物的药物组合物，但是此类四苯乙烯衍生物的最低抑菌浓度和最低杀菌浓度最小为0.08μg/mL，抗菌能力偏低。
因此，新型的抗菌药物亟待开发。
发明内容
针对现有技术存在的不足，本发明的目的在于提供一种多臂AIE分子在制备抗菌药物中的用途和抗菌药物。该抗菌药物具有广谱的抗菌能力，能够有效抑制细菌生长，杀死高浓度细菌，并且可以清除成熟生物膜中的细菌，治疗多药耐药细菌引起的体内感染。
为达此目的，本发明采用以下技术方案：
第一方面，本发明提供一种多臂AIE分子在制备抗菌药物中的用途，所述多臂AIE分子具有一个核心结构和与所述核心结构相连的至少2个共轭刚性臂结构。
AIE分子是一类具有聚集诱导发光特性的分子，常用作检测离子、气体、有机小分子、爆炸物、蛋白、酶等的化学/生物传感器，或者用于生物体内成像。发明人通过研究发现，具有多个共轭刚性臂结构的AIE分子可以将其共轭刚性臂结构插入细菌的细胞壁中，通过阻碍转糖和转肽过程来影响细菌细胞壁合成，从而抑制或杀灭细菌，具有广谱的抗菌功能。
作为本发明的优选技术方案，所述共轭刚性臂结构选自 中的一种，其中表示基团的接入位置。
优选地，所述多臂AIE分子中共轭刚性臂结构的个数为2-6个；例如可以是2个、3个、4个、5个或6个。
作为本发明的优选技术方案，所述核心结构选自单键、碳原子、氮原子、硫原子、硅原子、-N＝N-、苯环、嘧啶环吡嗪环三嗪环 中的一种，其中表示基团的接入位置。
优选地，所述核心结构为单键、碳原子、氮原子、硫原子、硅原子、苯环、嘧啶环、吡嗪环或三嗪环。具有该核心结构的多臂AIE分子具有比其他多臂AIE分子更好的抗菌效果
作为本发明的优选技术方案，所述多臂AIE分子为如下分子中的一种：
多臂AIE分子可以根据本领域公知的方法进行合成，以分子9为例，其合成路线如下：
作为本发明的优选技术方案，所述多臂AIE分子的浓度≥0.008μg/mL；例如可以是0.008μg/mL、0.009μg/mL、0.01μg/mL、0.02μg/mL、0.03μg/mL、0.04μg/mL、0.05μg/mL、0.06μg/mL、0.08μg/mL、0.1μg/mL、0.2μg/mL、0.3μg/mL、0.5μg/mL、0.6μg/mL、0.8μg/mL、1μg/mL、2μg/mL、3μg/mL、5μg/mL、6μg/mL、8μg/mL或10μg/mL等。
需要说明的是，上述“多臂AIE分子的浓度”是指细菌所处环境中的多臂AIE分子的浓度。
作为本发明的优选技术方案，所述多臂AIE分子用于抗革兰氏阳性菌和/或革兰氏阴性菌。
所述革兰氏阳性菌包括但不限于S.aureus(金黄色葡萄球菌)、MRSA(耐甲氧西林金黄色葡萄球菌)、S.epidermidis(表皮葡萄球菌)、MRSE(耐甲氧西林表皮葡萄球菌)、B.subtilis(枯草芽孢杆菌)、E.faecium(肠球菌)和MDR E.faecium(多重耐药肠球菌)。
所述革兰氏阴性菌包括但不限于E.coli(大肠杆菌)、P.aeruginosa(铜绿假单胞菌)、K.peneumoniae(肺炎克雷伯菌)、A.baumanii(鲍曼不动杆菌)、MDR E.coli(多药耐药大肠杆菌)、MDR P.aeruginosa(多药耐药铜绿假单胞菌)、MDR K.peneumoniae(多药耐药肺炎克雷伯菌)。
第二方面，本发明提供一种抗菌药物，包括至少一种多臂AIE分子和分散介质；
每种所述多臂AIE分子具有一个核心结构和与所述核心结构相连的至少2个共轭刚性臂结构。
作为本发明的优选技术方案，所述共轭刚性臂结构选自 中的一种，其中表示基团的接入位置。
优选地，所述多臂AIE分子中共轭刚性臂结构的个数为2-6个；例如可以是2个、3个、4个、5个或6个等。
优选地，所述核心结构选自单键、碳原子、氮原子、硫原子、硅原子、-N＝N-、苯环、嘧啶环吡嗪环三嗪环 中的一种，其中表示基团的接入位置，进一步优选为单键、碳原子、氮原子、硫原子、硅原子、苯环、嘧啶环、吡嗪环或三嗪环。
优选地，所述多臂AIE分子选自如下分子：
作为本发明的优选技术方案，所述分散介质为液体分散介质或固体分散介质。
本发明对分散介质的种类没有特殊限制，其满足使得所述多臂AIE分子能够稳定存在并分散即可。示例性地，所述液体分散介质可以选择超纯水、生理盐水、磷酸盐缓冲液、培养基、四氢呋喃、N,N-二甲基甲酰胺、乙酸乙酯或己烷中的一种或至少两种的混合物；
所述固体分散介质可以选择聚乙二醇、聚乙烯基吡咯烷酮(PVP)、甘露醇、木糖醇、山梨醇、乙基纤维素或醋酸纤维素邻苯二甲酸酯中的一种或至少两种的混合物。
优选地，所述抗菌药物还包括任意药学上可接受的辅料。
本发明对辅料的种类没有特殊限制，本领域技术人员可根据需要进行选择。示例性地，所述辅料可以选择崩解剂、润滑剂、润湿剂、悬浮剂或矫味剂中的一种或至少两种的组合。
本发明中，对所述抗菌药物的使用方式没有特殊限制，其可以制备成任意形式的抗菌制品，例如消毒液、注射液、口服药片/药剂、伤口敷料或抗菌涂层等。
与现有技术相比，本发明具有以下有益效果：
发明人通过研究发现，具有多个共轭刚性臂结构的AIE分子可以将其共轭刚性臂结构插入细菌的细胞壁中，阻碍细胞壁的转糖和转肽过程，从而抑制或杀灭细菌，因此可以用于制备抗菌药物。
本发明提供的包含多臂AIE分子的抗菌药物具有广谱抗菌功能，具有良好的抑菌和杀菌活性，可以有效抑制细菌生长，快速杀死高浓度的细菌，并且可以清除成熟生物膜中的细菌，最低抑菌浓度(MIC)最低可达到0.008μg/mL，在多药耐药细菌的体内感染模型中，其具有良好的治疗效果，可以促进伤口愈合，治疗腹腔感染，治愈率达到100％。该抗菌药物可以用于日常用品或医疗器械的杀菌消毒，化妆品的抗菌处理，或者感染类疾病(如皮肤感染、腹腔感染、肺部感染、脑膜炎等)的预防和治疗。
附图说明
图1为不同多臂AIE分子的抑菌效果曲线图；
其中，添加各多臂AIE分子的菌液的OD600值在24小时内均无变化，各多臂AIE分子的抑菌效果曲线重叠在一起；
图2为不同多臂AIE分子的杀菌效果曲线图；
图3为不同浓度的多臂AIE分子9处理后的成熟生物膜中的相对活菌数量柱状图；
图4为不同多臂AIE分子处理的腹腔感染MRSA的小鼠的存活率柱状图；
图5为不同多臂AIE分子处理后的伤口感染MRSA的大鼠的伤口照片；
图6为不同多臂AIE分子处理后的伤口感染MRSA的大鼠伤口组织处的细菌数量柱状图。
具体实施方式
下面通过具体实施例来进一步说明本发明的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。
实施例1
多臂AIE分子的最低抑菌浓度(MIC)测定：
将多臂AIE分子加入到DMSO中(浓度为4096μg/mL)，超声使得分子充分溶解，然后用超纯水将得到的多臂AIE分子的DMSO溶液快速稀释至8μg/mL，备用。更换不同的多臂AIE分子，即可得到不同的多臂AIE分子溶液。
选用七种不同的革兰氏阳性菌S.aureus、MRSA、S.epidermidis、MRSE、B.subtilis、E.faecium和MDR E.faecium和七种不同的革兰氏阴性菌E.coli、P.aeruginosa、K.peneumoniae、A.baumani、MDR E.coli、MDR P.aeruginosa、MDRK.peneumoniae来进行测定。向96孔板每孔中加入100μL细菌培养基，然后向每排第一个孔中加入100μL，8μg/mL的多臂AIE分子溶液，混合均匀后取100μL加入到第二个孔中，依次梯度稀释至第11个孔(浓度依次为4、2、1、0.5、0.25、0.125、0.0625、0.0313、0.0156、0.008和0.004μg/mL)，最后一个孔中不加药物作为对照组。向每个孔中加入10μL浓度为105cfu/mL的细菌溶液(同一排孔中的细菌种类相同)。然后将上述96孔板在37℃培养箱中培养24h，并观察细菌生长情况。能够导致细菌不生长的最低药物浓度即为该药物的最小抑菌浓度MIC。
各多臂AIE分子对不同细菌的MIC值(单位μg/mL)如下表1和表2所示：
表1
表2
实施例2
多臂AIE分子的抑菌活性测试：
选取分子8、分子9、分子15、分子21和分子25进行测试。将浓度为104cfu/mL的MRSA细菌在添加有多臂AIE分子的LB培养基(多臂AIE分子终浓度为0.25μg/mL)和普通LB培养基(对照组)中培养，在不同时间点(4、8、12、16、20和24h)用紫外分光光度计测定菌液在600nm处的吸光度(OD600)，吸光度越大，表明细菌数量越多。绘制OD600随时间变化的曲线，作为细菌生长曲线，结果如图1所示。
结果显示，添加多臂AIE分子的菌液的OD600值在24h后没有变化，而对照组的OD600值明显升高，表明多臂AIE分子可以有效抑制细菌生长。
实施例3
多臂AIE分子的杀菌活性测试：
选取分子8、分子9、分子15、分子21和分子25进行测试。用LB培养基将MRSA细菌稀释到浓度为106cfu/mL左右，然后向菌液中加入多臂AIE分子溶液(终浓度为2μg/mL，不加药物组作为对照组)，在37℃振荡箱中进行培养，分别在4、8、12、16和24h时取部分菌液涂在固体培养基上，在37℃下培养24h，记录菌落数量。根据菌落数量计算细菌浓度变化，并绘制细菌浓度随时间的变化曲线，作为杀菌曲线，结果如图2所示。
由图2可以看出，对照组的细菌数量先随时间增加，12h后基本保持不变，而添加多臂AIE分子的菌液中细菌数量随时间减少，表明多臂AIE分子可以有效杀灭细菌。其中，分子25处理的细菌的数量在8h后减少至初始的0.01％以下，杀菌效率最高；分子9和分子21处理的细菌的数量在12h后减少至初始的0.01％以下；分子15处理的细菌的数量在24h后减少至初始的0.01％以下；分子8处理的细菌的数量在24h后减少至初始的0.1％以下，杀菌效率最低。
实施例4
多臂AIE分子对成熟生物膜中细菌的清除作用：
在96孔板中加入100μL浓度为105cfu/mL的S.aureus菌液，在37℃培养箱培养24h使其长出成熟生物膜。然后向其中加入100μL不同浓度(分别为0.31、0.63、1.25、2.5、5、10、20、40和80μg/mL)的多臂AIE分子9溶液和生理盐水(对照组)并孵育24h，去除上清液，用缓冲液洗板两次，再向其中加入测定细菌存活率的商用荧光染料fluorescein diacetate(FDA)，采用荧光分光光度计测定荧光强度，根据染料荧光强度计算生物膜中的相对活菌数量(以对照组细菌数量为100％)，结果如图3所示。
由图3可以看出，与对照组相比，添加分子9的实验组生物膜中活菌数量显著降低，并且随着分子9浓度的增加，活菌数量逐渐降低，表明多臂AIE分子可以有效清除成熟生物膜中的细菌。
实施例5
多臂AIE分子对小鼠腹腔感染的治疗：
取54只小鼠，分为9组，每组6只。向每只小鼠腹腔内注射500μL浓度为108cfu/mL的MRSA菌液。30min后，选择4组通过尾静脉注射100μL分子21的溶液(以分子21计，每组小鼠的注射剂量分别为0.13、0.25、0.5、1mg/kg)；选择4组通过尾静脉注射100μL分子9的溶液(以分子9计，每组小鼠的注射剂量分别为0.13、0.25、0.5、1mg/kg)；最后一组通过尾静脉注射100μL生理盐水作为对照。3天后观察小鼠生长情况并记录小鼠存活率，结果如图4所示。
由图4可以看出，对照组的小鼠存活率为0％，而注射了0.5mg/kg分子21和1mg/kg分子9溶液的腹腔感染MRSA的小鼠存活率为100％，表明多臂AIE分子具有良好的体内抗菌作用，治疗小鼠腹腔感染。
实施例6
多臂AIE分子对大鼠伤口感染的治疗：
取9只大鼠，分为3组，每组3只。将每只大鼠背部剪出直径为2cm的圆形伤口，然后在伤口处涂抹100μL浓度为108cfu/mL的MRSA细菌溶液。伤口感染30min后，分别用浸有分子9溶液(浓度16μg/mL)、分子21溶液(浓度16μg/mL)和生理盐水的纱布(对照组)处理伤口。2周后观察伤口愈合情况，记录伤口大小，并且在1周和2周时，将部分大鼠伤口组织剪下，研磨，并将研磨液涂在固体培养基上培养24h，根据菌落数量计算伤口组织处的细菌数量。其中，分子9和分子21处理的大鼠伤口愈合情况如图5所示，大鼠伤口组织处的细菌数量如图6所示。
由图5可以看出，对照组大鼠的伤口没有愈合，而经多臂AIE分子处理的大鼠伤口在2周后基本愈合；由图6可以看出，对照组大鼠伤口组织处的细菌数量减少不明显，而经分子9和分子21处理的大鼠伤口组织处的细菌数量明显减少。表明多臂AIE分子能够有效杀灭细菌，促进细菌感染的伤口的愈合。
申请人声明，以上所述仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，所属技术领域的技术人员应该明了，任何属于本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，均落在本发明的保护范围和公开范围之内。

Claims (10)

1.一种多臂AIE分子在制备抗菌药物中的用途，其特征在于，所述多臂AIE分子具有一个核心结构和与所述核心结构相连的至少2个共轭刚性臂结构。
2.根据权利要求1所述的用途，其特征在于，所述共轭刚性臂结构选自 中的一种，其中表示基团的接入位置；
优选地，所述多臂AIE分子中共轭刚性臂结构的个数为2-6个。
3.根据权利要求1或2所述的用途，其特征在于，所述核心结构选自单键、碳原子、氮原子、硫原子、硅原子、-N＝N-、苯环、嘧啶环、吡嗪环、三嗪环、 中的一种，其中表示基团的接入位置；
优选地，所述核心结构为单键、碳原子、氮原子、硫原子、硅原子、苯环、嘧啶环、吡嗪环或三嗪环。
4.根据权利要求1-3任一项所述的用途，其特征在于，所述多臂AIE分子为如下分子中的一种：
5.根据权利要求1-4任一项所述的用途，其特征在于，所述多臂AIE分子的浓度≥0.008μg/mL。
6.根据权利要求1-5任一项所述的用途，其特征在于，所述多臂AIE分子用于抗革兰氏阳性菌和/或革兰氏阴性菌。
7.一种抗菌药物，其特征在于，所述抗菌药物包括至少一种多臂AIE分子和分散介质；
每种所述多臂AIE分子具有一个核心结构和与所述核心结构相连的至少2个共轭刚性臂结构。
8.根据权利要求7所述的抗菌药物，其特征在于，所述共轭刚性臂结构选 中的一种，其中表示基团的接入位置；
优选地，所述多臂AIE分子中共轭刚性臂结构的个数为2-6个；
优选地，所述核心结构选自单键、碳原子、氮原子、硫原子、硅原子、-N＝N-、苯环、嘧啶环、吡嗪环、三嗪环、 中的一种，其中表示基团的接入位置，进一步优选为单键、碳原子、氮原子、硫原子、硅原子、苯环、嘧啶环、吡嗪环或三嗪环。
9.根据权利要求7或8所述的抗菌药物，其特征在于，所述多臂AIE分子选自如下分子：
10.根据权利要求7-9任一项所述的抗菌药物，其特征在于，所述分散介质为液体分散介质或固体分散介质；
优选地，所述抗菌药物还包括任意药学上可接受的辅料。
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