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Targeting nucleic acid phase transitions as a mechanism of action for antimicrobial peptides

Author

Listed:
  • Tomas Sneideris

    (University of Cambridge)

  • Nadia A. Erkamp

    (University of Cambridge)

  • Hannes Ausserwöger

    (University of Cambridge)

  • Kadi L. Saar

    (University of Cambridge)

  • Timothy J. Welsh

    (University of Cambridge)

  • Daoyuan Qian

    (University of Cambridge)

  • Kai Katsuya-Gaviria

    (University of Cambridge)

  • Margaret L. L. Y. Johncock

    (University of Cambridge)

  • Georg Krainer

    (University of Cambridge)

  • Alexander Borodavka

    (University of Cambridge)

  • Tuomas P. J. Knowles

    (University of Cambridge
    University of Cambridge)

Abstract

Antimicrobial peptides (AMPs), which combat bacterial infections by disrupting the bacterial cell membrane or interacting with intracellular targets, are naturally produced by a number of different organisms, and are increasingly also explored as therapeutics. However, the mechanisms by which AMPs act on intracellular targets are not well understood. Using machine learning-based sequence analysis, we identified a significant number of AMPs that have a strong tendency to form liquid-like condensates in the presence of nucleic acids through phase separation. We demonstrate that this phase separation propensity is linked to the effectiveness of the AMPs in inhibiting transcription and translation in vitro, as well as their ability to compact nucleic acids and form clusters with bacterial nucleic acids in bacterial cells. These results suggest that the AMP-driven compaction of nucleic acids and modulation of their phase transitions constitute a previously unrecognised mechanism by which AMPs exert their antibacterial effects. The development of antimicrobials that target nucleic acid phase transitions may become an attractive route to finding effective and long-lasting antibiotics.

Suggested Citation

  • Tomas Sneideris & Nadia A. Erkamp & Hannes Ausserwöger & Kadi L. Saar & Timothy J. Welsh & Daoyuan Qian & Kai Katsuya-Gaviria & Margaret L. L. Y. Johncock & Georg Krainer & Alexander Borodavka & Tuoma, 2023. "Targeting nucleic acid phase transitions as a mechanism of action for antimicrobial peptides," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42374-4
    DOI: 10.1038/s41467-023-42374-4
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    References listed on IDEAS

    as
    1. William E. Arter & Runzhang Qi & Nadia A. Erkamp & Georg Krainer & Kieran Didi & Timothy J. Welsh & Julia Acker & Jonathan Nixon-Abell & Seema Qamar & Jordina Guillén-Boixet & Titus M. Franzmann & Dav, 2022. "Biomolecular condensate phase diagrams with a combinatorial microdroplet platform," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Georg Krainer & Timothy J. Welsh & Jerelle A. Joseph & Jorge R. Espinosa & Sina Wittmann & Ella Csilléry & Akshay Sridhar & Zenon Toprakcioglu & Giedre Gudiškytė & Magdalena A. Czekalska & William E. , 2021. "Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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