A VersaTile-driven platform for rapid hit-to-lead development of engineered lysins
A VersaTile-driven platform for rapid hit-to-lead development of engineered lysins
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DOI：
10.1126/sciadv.aaz1136
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发表时间：
2020-06-01
期刊：
影响因子：
13.6
通讯作者：
Briers, Y.
中科院分区：
文献类型：
--
作者：
Gerstmans, H.;Grimon, D.;Briers, Y.
卫生保健当局正在呼吁新的抗菌疗法，以科普全球出现的抗药性细菌。噬菌体编码的溶素是一类独特的抗菌药物，具有很好的临床前进展。溶素的定制工程允许产生针对潜在的任何细菌病原体的变体。在这里，我们提出了一个高通量的命中领先的开发平台，工程赖氨酸。该平台由VersaTile驱动，VersaTile是一种新的DNA组装方法，用于快速构建工程化溶素的组合文库。我们构建了大约10，000个溶素变体。使用迭代筛选程序，我们确定了一个领先的变种，对鲍曼不动杆菌在人血清和体外猪烧伤创面模型的抗菌活性高。这个通用平台可以提供新的机会，用工程化的溶素填充临床前管道，用于各种（治疗）应用。
Health care authorities are calling for new antibacterial therapies to cope with the global emergence of antibiotic-resistant bacteria. Bacteriophage-encoded lysins are a unique class of antibacterials with promising (pre)clinical progress. Custom engineering of lysins allows for the creation of variants against potentially any bacterial pathogen. We here present a high-throughput hit-to-lead development platform for engineered lysins. The platform is driven by VersaTile, a new DNA assembly method for the rapid construction of combinatorial libraries of engineered lysins. We constructed approximately 10,000 lysin variants. Using an iterative screening procedure, we identified a lead variant with high antibacterial activity against Acinetobacter baumannii in human serum and an ex vivo pig burn wound model. This generic platform could offer new opportunities to populate the preclinical pipeline with engineered lysins for diverse (therapeutic) applications.