中文摘要：噬菌体的高特异性受其受体结合蛋白(RBP)驱动。许多克雷伯氏菌噬菌体以荚膜外多糖为受体，编码具有解聚酶活性的RBP。这些RBP的模块化结构具有一个将RBP连接到噬菌体尾部的N-末端结构模块和一个用于胞外多糖降解的C-末端特异性模块，支持水平转移是克雷伯氏菌噬菌体RBP的主要进化驱动因素。本研究通过构建模块化RBP嵌合体，交换N-端结构模块和C-端特异性模块来模拟这种自然进化过程。所有嵌合体均严格遵循C-末端模块的荚膜血清型特异性。将带有K11 N-末端结构RBP模块的嵌合体移植到克雷伯氏菌噬菌体K11支架中，可产生荚膜血清型转换和相应的宿主范围修饰，证明C-末端特异性模块的水平转移为克雷伯菌噬菌体提供了一条快速适应新荚膜血清型的进化道路。
重点：抗菌素耐药性危机重新点燃了人们对噬菌体治疗的兴趣。研究用噬菌体治疗细菌感染已经一个多世纪，但其高特异性仍然是治疗干预的最大障碍之一。特别是许多克雷伯氏菌噬菌体的宿主范围很窄，受到保护细菌的高度多样性胞外多糖荚膜的限制。本文阐述了克雷伯菌噬菌体如何通过交换其受体结合蛋白的构建块来对付这种高多样性。
外文摘要：The high specificity of bacteriophages is driven by their receptor-binding proteins (RBPs). Many Klebsiella bacteriophages target the capsular exopolysaccharide as the receptor and encode RBPs with depolymerase activity. The modular structure of these RBPs with an N-terminal structural module to attach the RBP to the phage tail, and a C-terminal specificity module for exopolysaccharide degradation, supports horizontal transfer as a major evolutionary driver for Klebsiella phage RBPs. We mimicked this natural evolutionary process by the construction of modular RBP chimeras, exchanging N-terminal structural modules and C-terminal specificity modules. All chimeras strictly follow the capsular serotype specificity of the C-terminal module. Transplanting chimeras with a K11 N-terminal structural RBP module in a Klebsiella phage K11 scaffold results in a capsular serotype switch and corresponding host range modification of the synthetic phages, demonstrating that horizontal transfer of C-terminal specificity modules offers Klebsiella phages an evolutionary highway for rapid adaptation to new capsular serotypes.
   IMPORTANCE The antimicrobial resistance crisis has rekindled interest in bacteriophage therapy. Phages have been studied over a century as therapeutics to treat bacterial infections, but one of the biggest challenges for the use of phages in therapeutic interventions remains their high specificity. In particular, many Klebsiella phages have a narrow spectrum constrained by the high diversity of exopolysaccharide capsules that shield access to the cells. In this work, we have elaborated how Klebsiella phages deal with this high diversity by exchanging building blocks of their receptor-binding proteins.
外文关键词：bacteriophage；Klebsiella；depolymerase；horizontal transfer；receptor-binding protein
作者：Latka, A；Lemire, S；Grimon, D；Dams, D；Maciejewska, B；Lu, T；Drulis-Kawa, Z；Briers, Y
作者单位：Univ Ghent；Univ Wroclaw；MIT；Broad Inst；Singapore MIT Alliance Res & Technol；Armata Pharmaceut
期刊名称：MBIO
期刊影响因子：4.778
出版年份：2021
出版刊次：3
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