近日，美国麻省理工学院Timothy K. Lu团队通过噬菌体尾部纤维突变进行工程化改造噬菌体宿主范围，从而实现对细菌抗性的抑制。这一研究成果发表在2019年10月3日出版的国际学术期刊《细胞》上。

通过自然进化和结构建模，研究人员在T3噬菌体尾巴纤维蛋白中鉴定了宿主范围决定区（HRDR），并开发了高通量策略以通过定点诱变对这些区域进行遗传工程改造。受抗体特异性工程的启发，这种方法可产生深层的功能多样性，同时最大程度地减少对整个尾部纤维结构的破坏，从而产生合成的“噬菌体”。

研究人员发现，突变HRDR会产生宿主范围改变的噬菌体，而筛选出的噬菌体可实现对体外细菌生长的长期抑制，这是通过防止耐药性的出现所实现的，并且使用鼠模型可在体内起作用。

研究人员预计，这种方法可能会促进下一代抗微生物药物的产生，从而减缓耐药性的发展，并可能扩展到其他病毒载体，从而具有广泛的应用范围。

据了解，抗生素耐药性感染的迅速出现促使人们对基于噬菌体的抗菌素的兴趣日益浓厚。然而，细菌获得抗药性是成功开发噬菌体疗法的主要问题。

附：英文原文

Title: Engineering Phage Host-Range and Suppressing Bacterial Resistance through Phage Tail Fiber Mutagenesis

Author: Kevin Yehl, Sébastien Lemire, Andrew C. Yang, Hiroki Ando, Mark Mimee, Marcelo Der Torossian Torres, Cesar de la Fuente-Nunez, Timothy K. Lu

Issue&Volume: 2019/10/03

Abstract: The rapid emergence of antibiotic-resistant infections is prompting increased interest in phage-based antimicrobials. However, acquisition of resistance by bacteria is a major issue in the successful development of phage therapies. Through natural evolution and structural modeling, we identified host-range-determining regions (HRDRs) in the T3 phage tail fiber protein and developed a high-throughput strategy to genetically engineer these regions through site-directed mutagenesis. Inspired by antibody specificity engineering, this approach generates deep functional diversity while minimizing disruptions to the overall tail fiber structure, resulting in synthetic “phagebodies.” We showed that mutating HRDRs yields phagebodies with altered host-ranges, and select phagebodies enable long-term suppression of bacterial growth in vitro, by preventing resistance appearance, and are functional in vivo using a murine model. We anticipate that this approach may facilitate the creation of next-generation antimicrobials that slow resistance development and could be extended to other viral scaffolds for a broad range of applications.

DOI: 10.1016/j.cell.2019.09.015

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31022-0