噬菌体疗法在胞内病原菌治疗中的挑战与思考  

Application of phage therapy in the treatment of intracellular pathogens

作　　者：王凯 张婉 黄云海 张立新 娄春波 WANG Kai;ZHANG Wan;HUANG Yunhai;ZHANG Lixin;LOU Chunbo(Cell and Gene Circuit Design Center,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518000,Guangdong,China;WuXi Biologics(Shanghai)Co.,Ltd,Shanghai 200131,China;State key Laboratory of Bioreactor Engineering,School of Biological Engineering,East China University of Science and Technology,Shanghai 200237,China)

机构地区：[1]中国科学院深圳先进技术研究院,细胞与基因线路设计中心,广东深圳518000 [2]上海药明生物技术有限公司,上海200131 [3]华东理工大学生物工程学院,生物反应器工程国家重点实验室,上海200237

出　　处：《合成生物学》2023年第4期676-689,共14页Synthetic Biology Journal

基　　金：国家自然科学基金[31720103901];国家自然科学基金青年科学基金(32100145);国家重点研发计划[2020YFA0907800];“111”计划(B18022)。

摘　　要：胞内病原菌是一类可以侵入并在哺乳动物细胞内生存的病原菌,它们可以调节宿主细胞内环境以便自身繁衍扩散。由于细胞膜等结构的保护,胞内病原菌在细胞内不容易被药物接触到,且容易积累耐药性,使得胞内病原菌的治疗成为一个悬而未决的难题,亟需新的治疗方法。噬菌体疗法是利用噬菌体裂解细菌治疗病原菌感染的手段。由于其不会对动物细胞产生危害,已经被广泛用于治疗病原细菌的胞外感染,同时为胞内病原菌的治疗提供了行之有效的新思路。本文介绍了细胞内病原体侵入和定居在真核细胞中的策略,以及它们对抗生素的抗性机制。噬菌体疗法具有独特的杀菌机制及突出的优势,因此噬菌体疗法在处理细胞内病原体特别是耐药病原体方面有巨大潜力。但噬菌体疗法在治疗细胞内病原体方面的应用仍面临许多挑战,如噬菌体不能轻易穿过真核细胞膜与细胞内病原体接触。最后,讨论了噬菌体疗法在治疗细胞内耐药病原体方面可能的发展方向。未来需解决噬菌体入胞难题,通过细胞穿透肽修饰或纳米材料修饰,使噬菌体能够有效地进入真核细胞。在此基础上,可以对噬菌体本身进行改造,获得杀菌效果更强的重组噬菌体,并进一步挖掘包括温和噬菌体在内的噬菌体资源。Intracellular pathogens are a class of pathogens that can invade eukaryotic cells and survive in cells.After entering the host cell,they can regulate the intracellular environment so as to facilitate their own reproduction and spread,while the host’s cell membrane and other structures will protect intracellular pathogens from being attacked by antibiotics,resulting in treatment failure.the increasingly serious drug resistance of intracellular pathogens makes the problem more difficult.It is necessary to explore bacteriostatic methods other than antibiotics,and phage therapy is a good choice.Bacteriophages have been used to treat bacterial infections as early as their discovery because they can effectively kill extracellular pathogens.However,phage therapy to deal with intracellular pathogens is still in the exploratory stage.In this review,we introduce the strategies of intracellular pathogens invading and settling in eukaryotic cells,as well as the mechanism of their resistance to antibiotics.It shows the unique bactericidal mechanism of phage therapy and its outstanding advantages,and the great potential of phage therapy in dealing with intracellular pathogens,especially drug-resistant pathogens.Of course,the application of phage therapy in the treatment of intracellular pathogens still faces many challenges,such as the fact that bacteriophages can not easily pass through the eukaryotic cell membrane to contact with intracellular pathogens.Finally,we discussed the possible development direction of bacteriophage therapy in the treatment of intracellular drug-resistant pathogens.We believe that first of all,we must adopt the“Trojan horse”strategy,cell-penetrating peptides modification or nanomaterial modification to make it possible for bacteriophages to enter eukaryotic cells efficiently.On this basis,the bacteriophage itself can be modified to obtain a recombinant bacteriophage with stronger bactericidal efficacy,and the bacteriophage resources,including mild bacteriophage,should be further explored.

关 键 词：胞内病原菌 耐药性 噬菌体 噬菌体疗法 跨膜运输 

分 类 号：Q816[生物学—生物工程]