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研究人员设计出新型抗菌肽 可杀死体内耐药细菌
新闻來源:【管理员】    发布时间:2019-08-20   浏览次数:888

 近日,美国丹娜-法伯癌症研究所Loren D. Walensky团队设计出稳定、无毒、能杀灭小鼠体内耐药细菌的抗菌肽。这一研究成果于2019年8月19日在线发表于《自然—生物技术》。


研究人员分析了的一个基于magainin II的文库,其含有58个AMP(StAMP),并利用结构-功能-毒性测量的信息,开发了一种稳定、抗蛋白酶、有效并且无毒的原型StAMP设计算法。 研究人员发现,一种名为Mag(i + 4)1,15(A9K,B21A,N22K,S23K)的StAMP可以杀死多耐药的革兰氏阴性病原体,如在小鼠腹膜炎-败血症模型中的粘菌素抗性鲍曼不动杆菌(Acinetobacter baumannii),并在小鼠毒性研究中没有观察到溶血或肾损伤。单独输入氨基酸序列,研究人员进一步生成了膜选择性的StAMP(pleurocidin、CAP18和esculentin),这体现了这一设计平台的普遍适用性。


据悉,阳离子α-螺旋抗菌肽(AMP)的临床转化受到结构不稳定、蛋白降解和非特异性膜裂解体内毒性的阻碍。虽然疏水性含量和电荷分布的相关分析使得合成AMP的设计增加了剂量并减少了体外溶血,但体内非特异性膜毒性仍然阻碍AMP药物开发。


附:英文原文

Title: Design of stapled antimicrobial peptides that are stable, nontoxic and kill antibiotic-resistant bacteria in mice

Author: Rida Mourtada, Henry D. Herce, Daniel J. Yin, Jamie A. Moroco, Thomas E. Wales, John R. Engen, Loren D. Walensky

Issue&Volume: 19 August 2019

Abstract: The clinical translation of cationic α-helical antimicrobial peptides (AMPs) has been hindered by structural instability, proteolytic degradation and in vivo toxicity from nonspecific membrane lysis. Although analyses of hydrophobic content and charge distribution have informed the design of synthetic AMPs with increased potency and reduced in vitro hemolysis, nonspecific membrane toxicity in vivo continues to impede AMP drug development. Here, we analyzed a 58-member library of stapled AMPs (StAMPs) based on magainin II and applied the insights from structure–function–toxicity measurements to devise an algorithm for the design of stable, protease-resistant, potent and nontoxic StAMP prototypes. We show that a lead double-stapled StAMP named Mag(i+4)1,15(A9K,B21A,N22K,S23K) can kill multidrug-resistant Gram-negative pathogens, such as colistin-resistant Acinetobacter baumannii in a mouse peritonitis–sepsis model, without observed hemolysis or renal injury in murine toxicity studies. Inputting the amino acid sequences alone, we further generated membrane-selective StAMPs of pleurocidin, CAP18 and esculentin, highlighting the generalizability of our design platform.

DOI: https://doi.org/10.1038/s41587-019-0222-z
Source:
https://www.nature.com/articles/s41587-019-0222-z

期刊信息
Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:31.864
官方网址:
https://www.nature.com/nbt/
投稿链接:
https://mts-nbt.nature.com/cgi-bin/main.plex

本文转自《科学网》-小柯机器人

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