CN109748949B - 一种抗菌肽及其应用 - Google Patents
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Abstract
本发明公开了一种抗菌肽及其应用,该抗菌肽包括氨基酸序列为Arg‑Trp‑Arg‑Phe‑NH2的多肽以及该多肽的拟肽,其中,多肽中的氨基酸为L‑型氨基酸或D‑型氨基酸,拟肽为多肽N端和/或C端修饰后的产物。该抗菌肽革兰氏阳性菌、革兰氏阴性菌具有广谱杀伤活性,并较天然抗菌肽有更强的杀菌活性,且对动、植物细胞无任何毒害作用,可以用其制备一种用于人体细菌感染的抗菌剂。
Description
技术领域
本发明属于多肽技术领域,具体涉及一种抗菌肽及其应用。
背景技术
自从抗生素发明以来,人类在控制和治疗微生物感染中取得了较大的成就,但随着目前抗生素的持续使用,微生物抗药性已成为微生物感染控制的重大问题,以至于某些微生物细菌已失去了一种使其被控制杀灭的新物质。如在临床药物治疗中,万古霉素抗性的葡萄球菌、肠球菌以及其他革兰氏阴性菌感染疾病目前均是世界范围内的临床难题。
抗菌肽是一类广泛存在于微生物及动植物体内的小分子多肽,通常由30多个氨基酸残基形成,分子量为2~7KDa。抗菌肽的杀菌机制在于它能破坏细菌的细胞膜,导致细胞内容物溢出,最终引起细菌死亡。抗菌肽因其具有的广泛的生物学活性,因此在医学上良好的应用前景。但现有天然抗菌肽在含量、抗菌活性、化学阳离子和溶血作用等方面还存在诸多缺陷。抗菌肽在动物体内含量极微,从动物体内提取抗菌肽产量低、费时长、工艺复杂、费用昂贵,这成为制约抗菌肽进入实际应用的最大障碍。
发明内容
本发明目的是提供一类抗菌活性强、成本相对较低、无溶血毒性的新型合成抗菌肽及其衍生物。
为了达到上述目的,本发明所采用的技术方案是:提供一种抗菌肽,该抗菌肽包括氨基酸序列为Arg-Trp-Arg-Phe-NH2的多肽以及该多肽的拟肽。
本发明中多肽的拟肽为多肽N端和/或C端修饰后的产物。
本发明制备出的抗菌肽具有很强的抗菌活性,而且不会表现出溶血毒性,可以用其制备一种用于人体细菌感染的抗菌剂。
本发明的有益效果是:本发明提供一种新的人工设计阳离子的抗菌肽,这些抗菌肽可方便地采用固相化学法编码抗菌肽的基因克隆到载体上,然后进入宿主细胞中表达后获得。该阳离子抗菌肽对革兰氏阳性菌、革兰氏阴性菌具有广谱杀伤活性,并较天然抗菌肽有更强的杀菌活性,且对动、植物细胞无任何毒害作用。
附图说明
图1为抗菌肽Core-A的质谱图;
图2为对照抗菌肽LfcinB6的质谱图。
具体实施方式
下面结合实施例对本发明的具体实施方式做详细的说明。
实施例一:目标产物Core-A和对照抗菌肽LfcinB6的固相合成
按照标准的Fmoc固相程序合成目标抗菌肽Core-A(Arg-Trp-Arg-Phe)和对照抗菌肽LfcinB6(Phe-Arg-Trp-Trp-Gln-Arg),合成从C端到N端逐个进行,由合成仪自动控制进行(多肽的合成操作见pioneer多肽合成仪操作指南)。合成的产物经过反相液相色谱(Vydac 218TP1022柱,2.2*25cm)纯化,采用乙腈/水体系洗脱并进行质谱分析,得到相应的抗菌肽。所制备出的Core-A多肽序列为:R-W-R-F-NH2(Arg-Trp-Arg-Phe-NH2)。
抗菌肽合成成功后,称量100mg干燥后的多肽,将其溶于10ml浓度为0.1%的三氟乙酸溶液中;然后用反相液相色谱进行纯化,反相液相色谱的流动相为:水(含0.1%三氟乙酸):乙腈=9:1,收集目标峰,冻干,得产品;再用MS确认所得产品是否准确,并用HPLC检测纯度。抗菌肽Core-A的质谱分析结果见图1所示。
制备出的抗菌肽Core-A经过质谱分析,发现其分子量为663.51,由多肽序列计算出的理论值为663.36;证明制备的多肽即为设计的Core-A抗菌肽。取鉴定合格的抗菌肽产物备用。
对照抗菌肽LfcinB6的合成与纯化方法与Core-A抗菌肽相同。对照抗菌肽LfcinB6的质谱分析结果见图2所示。
实施例二:抗菌肽的杀菌活性检测
采用琼脂板扩散法对Core-A抗菌肽和对照抗菌肽LfcinB6的杀菌活性进行检测,以评价本发明中核心序列Core-A的杀菌活性。抗菌肽的杀菌活性检测方法具体为:
先采用常规菌种复苏方法将菌种(革兰氏阳性菌和革兰氏阴性菌,购于中国生物制品检定所)复苏,并斜面接种,于37℃培养过夜;然后挑菌于普通的LB培养基中,37℃培养过夜;再稀释菌液使菌浓度为105~106cfu/ml,按每个平板100μl菌液接种于15ml LB固体培养皿中,待凝固后,涂布均匀后,打孔5mm,3个/平板,分别加入10μl浓度为1mg/ml的Core-A抗菌肽溶液、10μl浓度为1mg/ml的LfcinB6溶液和10μl超纯水(LfcinB6作为阳性对照,超纯水作为阴性对照),先于4℃条件下静置3h,再将平板置于37℃培养8h,测量抑菌圈大小,判定杀菌能力。结果见表1。
表1抗菌肽对不同细菌的抗菌活性的测定比较
注:“+”代表5mm,+越多,杀菌能力越强
从表1中可以看出,本发明中的抗菌肽Core-A杀菌能力显著且优于对照抗菌肽LfcinB6。
实施例二:抗菌肽的抑菌活性检测
采用96孔板法对Core-A抗菌肽和对照抗菌肽LfcinB6的抑菌活性进行检测,以评价本发明中核心序列Core-A的抑菌活性。抗菌肽的抑菌活性检测方法具体为:
先采用常规菌种复苏方法将菌种(革兰氏阳性菌和革兰氏阴性菌,购于中国生物制品检定所)复苏,并接种斜面,于37℃培养过夜;然后挑菌于普通LB培养基中,37℃培养过夜,稀释菌液使菌浓度为104~105cfu/ml,按每孔100μl菌液接种于96孔板中,将Core-A抗菌肽和对照抗菌肽LfcinB6按照连续稀释法稀释后,每孔中加入10μl,再将96孔板置于37℃条件下培养过夜,酶标仪检测OD620值。结果见表2。
表2抗菌肽对不同细菌的抗菌活性最小抑菌浓度(MIC)的比较
表2中最小抑菌浓度值越小,则代表抗菌能力越强。从上表看出,本发明的抗菌肽Core-A自身就具有抑菌能力,且MIC均比LfcinB6小,说明本发明的阳离子抗菌肽的抗菌能力远远强于对照抗菌肽LfcinB6。
实施例三:体外溶血活性检测
本实施例用于检测阳离子抗菌肽Core-A对动物红细胞是否具有溶血活性,并用对照抗菌肽LfcinB6作为对照。使用的血样取于脱纤维绵羊血。阳离子抗菌肽的溶血活性检测采用琼脂板空穴扩散法进行,具体的为:
将脱纤维绵羊血红细胞按照1:20的体积比加入40℃的LB培养液中,按每个平板15ml倾倒混合LB固体培养液,待凝固后,打孔5mm,4个/平板,分别加入50μl浓度为1mg/ml的阳离子抗菌肽Core-A溶液、LfcinB6溶液、吐温80及超纯水(吐温80作为阳性对照,超纯水作为阴性对照),先4℃静置3h,再将平板置于37℃培养24h,观察72h之内是否有溶血圈出现,判定是否有溶血作用。结果见表3。
表3抗菌肽72h内是否出现溶血圈判定抗菌肽有无溶血活性
从表中可以看出,本发明中的阳离子抗菌肽Core-A在1mg/ml浓度下,72h后都无溶血圈出现,即未表现出溶血毒性。表明抗菌肽Core-A在高浓度下也不会表现出溶血毒血,为研究和开发治疗细菌感染的药物实际应用奠定了成药的关键基础。
实施例四:体外溶血率检测
本实施例用于检测阳离子抗菌肽Core-A对动物红细胞的溶血率,并用对照抗菌肽LfcinB6作为对照。使用的血样取于脱纤维绵羊血。阳离子抗菌肽的溶血活率检测方法为:
红细胞经PBS(PBS:35mM磷酸缓冲液/0.15MNaCl,PH7.2)洗涤,取100μl的8%红细胞悬液于96孔板中,每孔加入100μl抗菌肽溶液,37℃条件下培养1h,1500rpm离心5分钟,转移100μl上清液于新的96孔板中,通过酶标仪检测414nm下的吸收,阴性对照用PBS溶液,阳性对照用0.1%Triton X-100溶液。检测结果见表4。
表4抗菌肽溶血活血检测结果
表中抗菌肽的溶血率值越小,则代表抗菌肽的溶血毒性越小。从表中可以看出阳离子抗菌肽Core-A的溶血率很低,相比于对照抗菌肽LfcinB溶血毒性非常低,特别是在高浓度下未有大幅度的溶血现象发生,为下步成药起了重要的作用。
虽然结合实施例对本发明的具体实施方式进行了详细地描述,但不应理解为对本专利的保护范围的限定。在权利要求书所描述的范围内,本领域技术人员不经创造性劳动即可作出的各种修改和变形仍属本专利的保护范围。
Claims (1)
1.具有Arg-Trp-Arg-Phe-NH2氨基酸序列的抗菌肽在制备抗菌剂中的应用,所述应用是指抑制枯草杆菌DB430和金黄色葡萄球菌CMCC26003的活性。
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WO2001098362A2 (en) * | 2000-06-16 | 2001-12-27 | Hercules Incorporated | Chemically-modified antimicrobial peptides, compositions and methods of production and use |
CN108586575A (zh) * | 2018-04-11 | 2018-09-28 | 福建省中科生物股份有限公司 | 一种多肽及其皮肤修复功能的应用 |
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US20030194445A1 (en) * | 2001-11-12 | 2003-10-16 | Kuhner Carla H. | Compositions and methods of use of peptides in combination with biocides and/or germicides |
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WO2001098362A2 (en) * | 2000-06-16 | 2001-12-27 | Hercules Incorporated | Chemically-modified antimicrobial peptides, compositions and methods of production and use |
CN108586575A (zh) * | 2018-04-11 | 2018-09-28 | 福建省中科生物股份有限公司 | 一种多肽及其皮肤修复功能的应用 |
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