IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57073-5.html
   My bibliography  Save this article

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

Author

Listed:
  • Hao Yan

    (China Agricultural University
    Chinese Academy of Sciences
    Beijing Key Laboratory of Genetic Element Biosourcing & Intelligent Design for Biomanufacturing)

  • Zhenguo Xin

    (Chinese Academy of Sciences)

  • Ziwei Sang

    (China Agricultural University
    Chinese Academy of Sciences)

  • 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
    Beijing Key Laboratory of Genetic Element Biosourcing & Intelligent Design for Biomanufacturing
    University of Chinese Academy of Sciences)

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.

Suggested Citation

  • Hao Yan & Zhenguo Xin & Ziwei Sang & Xingwang Li & Jia Xie & Jiale Wu & Shen Pang & Ying Wen & Weishan Wang, 2025. "A rational multi-target combination strategy for synergistic improvement of non-ribosomal peptide production," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57073-5
    DOI: 10.1038/s41467-025-57073-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57073-5
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-57073-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Alexander Koglin & Frank Löhr & Frank Bernhard & Vladimir V. Rogov & Dominique P. Frueh & Eric R. Strieter & Mohammad R. Mofid & Peter Güntert & Gerhard Wagner & Christopher T. Walsh & Mohamed A. Mara, 2008. "Structural basis for the selectivity of the external thioesterase of the surfactin synthetase," Nature, Nature, vol. 454(7206), pages 907-911, August.
    2. Anand V. Sastry & Ye Gao & Richard Szubin & Ying Hefner & Sibei Xu & Donghyuk Kim & Kumari Sonal Choudhary & Laurence Yang & Zachary A. King & Bernhard O. Palsson, 2019. "The Escherichia coli transcriptome mostly consists of independently regulated modules," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Arianna Miano & Kevin Rychel & Andrew Lezia & Anand Sastry & Bernhard Palsson & Jeff Hasty, 2023. "High-resolution temporal profiling of E. coli transcriptional response," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Donghui Choe & Connor A. Olson & Richard Szubin & Hannah Yang & Jaemin Sung & Adam M. Feist & Bernhard O. Palsson, 2024. "Advancing the scale of synthetic biology via cross-species transfer of cellular functions enabled by iModulon engraftment," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Arjun Patel & Dominic McGrosso & Ying Hefner & Anaamika Campeau & Anand V. Sastry & Svetlana Maurya & Kevin Rychel & David J. Gonzalez & Bernhard O. Palsson, 2024. "Proteome allocation is linked to transcriptional regulation through a modularized transcriptome," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Cosme Claverie & Francesco Coppolino & Maria-Vittoria Mazzuoli & Cécile Guyonnet & Elise Jacquemet & Rachel Legendre & Odile Sismeiro & Giuseppe Valerio Gaetano & Giuseppe Teti & Patrick Trieu-Cuot & , 2024. "Constitutive activation of two-component systems reveals regulatory network interactions in Streptococcus agalactiae," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Yichao Han & Wanji Li & Alden Filko & Jingyao Li & Fuzhong Zhang, 2023. "Genome-wide promoter responses to CRISPR perturbations of regulators reveal regulatory networks in Escherichia coli," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57073-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.