Cell-free biosynthesis and engineering of ribosomally synthesized lanthipeptides

Wan-Qiu Liu, Xiangyang Ji, Fang Ba, Yufei Zhang, Huiling Xu, Shuhui Huang, Xiao Zheng, Yifan Liu (), Shengjie Ling (), Michael C. Jewett () and Jian Li ()
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Wan-Qiu Liu: ShanghaiTech University
Xiangyang Ji: ShanghaiTech University
Fang Ba: ShanghaiTech University
Yufei Zhang: ShanghaiTech University
Huiling Xu: ShanghaiTech University
Shuhui Huang: ShanghaiTech University
Xiao Zheng: ShanghaiTech University
Yifan Liu: ShanghaiTech University
Shengjie Ling: ShanghaiTech University
Michael C. Jewett: Stanford University
Jian Li: ShanghaiTech University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural products with diverse chemical structures and potent biological activities. A vast majority of RiPP gene clusters remain unexplored in microbial genomes, which is partially due to the lack of rapid and efficient heterologous expression systems for RiPP characterization and biosynthesis. Here, we report a unified biocatalysis (UniBioCat) system based on cell-free gene expression for rapid biosynthesis and engineering of RiPPs. We demonstrate UniBioCat by reconstituting a full biosynthetic pathway for de novo biosynthesis of salivaricin B, a lanthipeptide RiPP. Next, we delete several protease/peptidase genes from the source strain to enhance the performance of UniBioCat, which then can synthesize and screen salivaricin B variants with enhanced antimicrobial activity. Finally, we show that UniBioCat is generalizable by synthesizing and evaluating the bioactivity of ten uncharacterized lanthipeptides. We expect UniBioCat to accelerate the discovery, characterization, and synthesis of RiPPs.

Date: 2024
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DOI: 10.1038/s41467-024-48726-y

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