A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide production

Hao Yan, Zhenguo Xin, Ziwei Sang, Xingwang Li, Jia Xie, Jiale Wu, Shen Pang, Ying Wen () and Weishan Wang ()
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Hao Yan: China Agricultural University
Zhenguo Xin: Chinese Academy of Sciences
Ziwei Sang: China Agricultural University
Xingwang Li: China Agricultural University
Jia Xie: China Agricultural University
Jiale Wu: China Agricultural University
Shen Pang: Chinese Academy of Sciences
Ying Wen: China Agricultural University
Weishan Wang: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Non-ribosomal peptides (NRPs) are pharmaceutically important natural products that include numerous clinical drugs. However, the biosynthesis of these NRPs is intricately regulated and improving production through manipulation of multiple regulatory targets remains largely empirical. We here develop a screening-based, multi-target rational combination strategy and demonstrate its effectiveness in enhancing the titers of three NRP drugs ˗ daptomycin, thaxtomin A and surfactin. Initially, we devise a reliable colorimetric analog co-expression and co-biosynthesis reporter system for screening high-yielding phenotypes. Subsequently, through coupling CRISPR interference to induce genome-wide differential expression, we identify dozens of repressors that inhibit the biosynthesis of these NRPs. To address the challenge of multi-target combination, we further developed a dual-target screen approach and introduced an interplay map based on the synergy coefficient of each pairwise interaction. Employing this strategy, we engineer the final strains with multi-target synergistic combination and achieve the titer improvement of the three NRPs. Our work provides a rational multi-target combination strategy for production improvement of NRPs.

Date: 2025
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DOI: 10.1038/s41467-025-57073-5

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