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通过深度挖掘元基因组动机来设计细菌菌体

Phil Huss^1,2,3, Kristopher Kieft^2,3, Anthony Meger¹

¹Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.

Science advances

|April 18, 2025

概括

一种新的方法,Meta-SIFT,识别了元基因组中的功能序列动机,以设计菌体活动. 这种工具成功地产生了具有新宿主特性的T7菌体变体,包括对大肠杆菌O121.

科学领域:

微生物学微生物学
生物信息学是一种生物信息学.
分子生物学分子生物学

背景情况:

细菌通过序列动机改变适应新宿主,但动机位置和健康优势往往是未知的.
工程菌体活动需要在庞大的元基因组数据集中识别功能序列动机.

研究的目的:

开发和验证一种新的方法,即元基因组序列信息功能评分 (Meta-SIFT),用于发现元基因组中的功能序列动图.
用Meta-SIFT识别的动机设计具有改变宿主特异性的菌体T7变体.
证明工程菌体对抗细菌病原体的治疗潜力.

主要方法:

开发了Meta-SIFT,集成深度突变扫描数据来创建用于挖矿元基因组的序列配置文件.
应用了Meta-SIFT来识别序列动图,并实验测试了T7菌体受体结合蛋白中的约17,000个动图.
在20个宿主和条件中评估T7变异特异性,重点关注动机位置,替代和位置偏好.

主要成果:

通过Meta-SIFT成功识别了功能序列动机,从而发现了数千种具有新型宿主特异性的T7变体.
来自不同遗传家族的动机赋予了特异性,位置,替代和位置的偏好决定了宿主范围.
改造的T7菌体变体对食源性病原体*Escherichia coli* O121表现出活性,显示出治疗潜力.

结论:

Meta-SIFT是一种强大的生物信息学工具,用于发现菌体转基因组中的功能动机.
该方法促进了为各种应用量身定制的宿主特征的菌体的工程.
这种方法释放了元基因组数据的潜力,以促进菌体治疗和合成生物学的发展.

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