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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2018, Vol. 38 Issue (11): 76-83    DOI: 10.13523/j.cb.20181110
综述     
抗菌环肽的研究进展 *
戈家傲1,刘畅1,龚建刚2,刘艳琴1,**()
1. 河北农业大学理工学院 沧州 061100
2. 河北农业大学食品科技学院 保定 071000
Research Progress of Antibacterial Cyclopeptides
Jia-ao GE1,Chang LIU1,Jian-gang GONG2,Yan-qin LIU1,**()
1. College of Science and Engineering, Agricultural University of Hebei, Cangzhou 061100, China
2. College of Food Science and Technology, Agricultural University of Hebei, Baoding 071000, China
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摘要：

鉴于禽类细菌性疾病对养禽业健康发展的不利影响,人们急需开发改善细菌耐药性的新型敏感性抗菌药物,使其达到治疗细菌性疾病的目的。环肽较线性肽因具有更多的生物活性和医药价值而成为抗菌药物的候选者。主要从天然抗菌环肽的发现、抗菌环肽的合成、环肽类抗菌药物的应用现状三个方面进行综述,期望有利于读者进一步了解抗菌环肽的研究概况,为开发新型抗菌环肽药物提供帮助。
关键词： 环肽;  抗菌活性;  抗菌机制;  细菌性疾病;  细菌耐药性    
Abstract:

In view of the adverse effects of avian bacterial diseases on the healthy development of the poultry industry, there is an urgent need to develop new sensitive antimicrobial agents that improve bacterial resistance so as to achieve the purpose of treating bacterial diseases. Cyclic peptides are candidates for antibacterials because they have more biological activities and medicinal properties than linear peptides. The discovery of natural antibacterial cyclic peptides, the synthesis of antibacterial cyclic peptides and the application status of antibacterial cyclic peptide drugs were mainly reviewed. It is expected to help readers to further understand the research situation of antibacterial cyclic peptides and provide assistance for the development of new antibacterial cyclic peptide drugs.
Key words: Cyclic peptides    Antibacterial activity    Antibacterial mechanism    Bacterial diseases    Bacterial drug resistance
收稿日期: 2018-06-04 出版日期: 2018-12-06
ZTFLH:  Q514+.3  
基金资助: * 河北农业大学留学博士专项资助项目(ZD201624)
通讯作者: 刘艳琴     E-mail: liuyqjiang@163.com
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戈家傲
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引用本文:

戈家傲,刘畅,龚建刚,刘艳琴. 抗菌环肽的研究进展 *[J]. 中国生物工程杂志, 2018, 38(11): 76-83.

Jia-ao GE,Chang LIU,Jian-gang GONG,Yan-qin LIU. Research Progress of Antibacterial Cyclopeptides. China Biotechnology, 2018, 38(11): 76-83.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20181110    或    https://manu60.magtech.com.cn/biotech/CN/Y2018/V38/I11/76

合成方法名称 基本原理 合成实物
生物合成 非核糖体方法即绕开核糖体,不使用mRNA作为模板、tRNA不作为携带工具,使用二十种氨基酸以外的其他化合物合成得到的环肽 天然青霉素
万古霉素
达托霉素
化学合成液相法 将脱保护后的线性肽前体直接在缩合剂的缩合下成环,也可将一端(一般为C端)先活化,然后成环 目前都采用固相法
化学合成固相法 先将要合成肽链末端氨基酸的羧基通过适当连接分子键合于不溶性高分子载体上,然后以此结合在固相载体上的氨基酸作为氨基组分,经过脱去氨基保护基并同过量的活化羧基组分反应接长肽链,达到所需要合成肽链的长度后,再选择适当试剂除去侧链保护基和从树脂上裂解产物 多黏菌素
Telavancin
化学合成二硫键法 两个游离的巯基经过氧化作用形成 S-S 共价键,而在生物体内的很多激素、酶当中也发现了二硫键的存在,并且二硫键的存在可以影响多肽的空间构象和生物活性,因此我们可以通过二硫键连接形成的环肽,并对环肽进行结构修饰,提高环肽的生物活性。 拟环状β防御素
基因工程 通过引入携带NRPS基因的表达质粒,合成达托霉素类脂肽的肽核心,随后与期望的酰基链偶合,可以生成一系列生物活性脂肽。 达托霉素A54145
组合合成 在相同条件下一次同步合成一系列化合物(亦称化合物库)。 Tyrocidine A类似物
表1  抗菌环肽合成方法对比
抗菌环肽名称 来源 抗菌对象 抗菌效果 抗菌机制 开发阶段
短杆菌肽S 从土壤细菌Aneurinibacillu migulanus中提取 治疗革兰氏阳性菌、革兰氏阴性菌及部分真菌引起的感染 表现出强烈的抗菌活性 破坏脂质膜和增强细菌细胞质膜的通透性 已上市
多黏菌素B 由多黏芽孢杆菌产生的一组多肽类抗生素 治疗革兰氏阴性菌(尤其是耐药性革兰氏阴性菌)引起的感染 只对大多数革兰氏阴性杆菌有效 三种说法:①破坏细胞膜;②因羟基自由基的积累破坏细菌DNA;③中和内毒素,抑制内毒素的释放及其活力,进一步达到抑制炎症因子释放 已上市
多黏菌素E 由某些细菌多黏类芽孢杆菌菌株产生的抗生素 治疗大多数革兰氏阴性杆菌引起的感染 只对大多数革兰氏阴性杆菌有效 与多黏菌素B作用机制相同 已上市
万古霉素 从采集Borneo土壤中的微生物发酵产物中分离得到 治疗革兰氏阳性菌引起的感染 对金黄色葡萄球菌、肺炎链球菌等作用强 抑制细胞壁合成 已上市
达托霉素 从玫瑰孢链霉菌(Streptomyces roseosporus)发酵液中提取得到 治疗革兰氏阳性菌引起的复杂皮肤感染和结构性皮肤感染 只对革兰氏阳性菌有杀菌作用 破坏细胞膜 已上市
Cubicin
(注射用达
托霉素)		 由玫瑰孢菌发酵产生的半合成抗生素 治疗由革兰氏阳性病原体引起的皮肤和皮肤结构感染 只对革兰氏阳性菌有杀菌作用 破坏细胞膜 已上市
Nisin 由乳酸乳球菌(Lactococcus lactis)产生的多环类抗菌肽 杀死或抑制引起食品腐败的革兰氏阳性菌 对产生孢子的细菌有很强的抑制作用 破坏细胞质膜 已上市
普那霉素 由始旋链霉菌产生的一种链阳性菌素类抗生素 治疗顽固性革兰氏阳性菌感染的特选药物 对大多数革兰氏阳性菌均具有较强的杀菌活性 抑制蛋白质合成 已上市
抗菌环肽名称 来源 抗菌对象 抗菌效果 抗菌机制 开发阶段
Telavancin 半合成的环脂糖肽类药物 治疗复杂性皮肤及皮肤结构感染/医院获得性感染 对常见皮肤软组织感染病原菌及引起肺炎的革兰氏阳性菌具有突出的体外抗菌活性 细菌细胞壁合成抑制剂 已上市
Dalbavancin 半合成的环脂糖肽类药物 治疗复杂性皮肤及皮肤结构感染 对革兰氏阳性菌具有优良的抗菌活性 细菌细胞壁合成抑制剂 已上市
Oritavancin 半合成的环脂糖肽类药物 治疗革兰氏阳性的皮肤感染 对革兰氏阳性具有抗菌活性 细菌细胞壁合成抑制剂 已上市
POL7080 使用阳离子抗菌肽ProtegrinⅠ作为出发点,对肽库进行迭代修改和筛选 治疗绿脓假单胞菌感染,革兰氏阴性菌感染 具有较强的抗菌活性 LptD同源蛋白抑制剂,抑制外膜的生物合成 Ⅱ期
表2  部分抗菌环肽药物的开发现状
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