生物
突变
抗生素耐药性
合成生物学
计算生物学
寄主(生物学)
噬菌体展示
细菌
蛋白质工程
遗传学
突变
基因
抗体
生物化学
酶
作者
Kevin Yehl,Sébastien Lemire,Andrew Yang,Hiromitsu Ando,Mark Mimee,Marcelo Der Torossian Torres,César de la Fuente-Núñez,Timothy K. Lu
出处
期刊:Cell
[Elsevier]
日期:2019-10-01
卷期号:179 (2): 459-469.e9
被引量:220
标识
DOI:10.1016/j.cell.2019.09.015
摘要
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.
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