A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide production
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 her...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57073-5 |
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| author | Hao Yan Zhenguo Xin Ziwei Sang Xingwang Li Jia Xie Jiale Wu Shen Pang Ying Wen Weishan Wang |
| author_facet | Hao Yan Zhenguo Xin Ziwei Sang Xingwang Li Jia Xie Jiale Wu Shen Pang Ying Wen Weishan Wang |
| author_sort | Hao Yan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1f5dca0c44a84062a3fee49044d4fa9e |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1f5dca0c44a84062a3fee49044d4fa9e2025-08-20T03:10:49ZengNature PortfolioNature Communications2041-17232025-02-0116111710.1038/s41467-025-57073-5A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide productionHao Yan0Zhenguo Xin1Ziwei Sang2Xingwang Li3Jia Xie4Jiale Wu5Shen Pang6Ying Wen7Weishan Wang8State Key Laboratory of Animal Biotech Breeding and College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of SciencesState Key Laboratory of Animal Biotech Breeding and College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding and College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding and College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding and College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of SciencesState Key Laboratory of Animal Biotech Breeding and College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of SciencesAbstract 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.https://doi.org/10.1038/s41467-025-57073-5 |
| spellingShingle | Hao Yan Zhenguo Xin Ziwei Sang Xingwang Li Jia Xie Jiale Wu Shen Pang Ying Wen Weishan Wang A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide production Nature Communications |
| title | A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide production |
| title_full | A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide production |
| title_fullStr | A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide production |
| title_full_unstemmed | A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide production |
| title_short | A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide production |
| title_sort | rational multi target combination strategy for synergistic improvement of non ribosomal peptide production |
| url | https://doi.org/10.1038/s41467-025-57073-5 |
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