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A scalable platform to discover antimicrobials of ribosomal origin

Author

Listed:
  • Richard S. Ayikpoe

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Chengyou Shi

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Alexander J. Battiste

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Sara M. Eslami

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Sangeetha Ramesh

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Max A. Simon

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Ian R. Bothwell

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Hyunji Lee

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Andrew J. Rice

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Hengqian Ren

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Qiqi Tian

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Lonnie A. Harris

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Raymond Sarksian

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Lingyang Zhu

    (University of Illinois at Urbana-Champaign)

  • Autumn M. Frerk

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Timothy W. Precord

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Wilfred A. Donk

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Douglas A. Mitchell

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Huimin Zhao

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

Abstract

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a promising source of new antimicrobials in the face of rising antibiotic resistance. Here, we report a scalable platform that combines high-throughput bioinformatics with automated biosynthetic gene cluster refactoring for rapid evaluation of uncharacterized gene clusters. As a proof of concept, 96 RiPP gene clusters that originate from diverse bacterial phyla involving 383 biosynthetic genes are refactored in a high-throughput manner using a biological foundry with a success rate of 86%. Heterologous expression of all successfully refactored gene clusters in Escherichia coli enables the discovery of 30 compounds covering six RiPP classes: lanthipeptides, lasso peptides, graspetides, glycocins, linear azol(in)e-containing peptides, and thioamitides. A subset of the discovered lanthipeptides exhibit antibiotic activity, with one class II lanthipeptide showing low µM activity against Klebsiella pneumoniae, an ESKAPE pathogen. Overall, this work provides a robust platform for rapidly discovering RiPPs.

Suggested Citation

  • Richard S. Ayikpoe & Chengyou Shi & Alexander J. Battiste & Sara M. Eslami & Sangeetha Ramesh & Max A. Simon & Ian R. Bothwell & Hyunji Lee & Andrew J. Rice & Hengqian Ren & Qiqi Tian & Lonnie A. Harr, 2022. "A scalable platform to discover antimicrobials of ribosomal origin," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33890-w
    DOI: 10.1038/s41467-022-33890-w
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    References listed on IDEAS

    as
    1. Cassandra Willyard, 2017. "The drug-resistant bacteria that pose the greatest health threats," Nature, Nature, vol. 543(7643), pages 15-15, March.
    2. Manuel A. Ortega & Yue Hao & Qi Zhang & Mark C. Walker & Wilfred A. van der Donk & Satish K. Nair, 2015. "Structure and mechanism of the tRNA-dependent lantibiotic dehydratase NisB," Nature, Nature, vol. 517(7535), pages 509-512, January.
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    Cited by:

    1. Haoyu Lang & Yuwen Liu & Huijuan Duan & Wenhao Zhang & Xiaosong Hu & Hao Zheng, 2023. "Identification of peptides from honeybee gut symbionts as potential antimicrobial agents against Melissococcus plutonius," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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