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Co-translational protein aggregation and ribosome stalling as a broad-spectrum antibacterial mechanism

Author

Listed:
  • Laleh Khodaparast

    (VIB Center for Brain and Disease Research
    KU Leuven)

  • Ladan Khodaparast

    (VIB Center for Brain and Disease Research
    KU Leuven)

  • Ramon Duran-Romaña

    (VIB Center for Brain and Disease Research
    KU Leuven)

  • Guiqin Wu

    (VIB Center for Brain and Disease Research
    KU Leuven)

  • Bert Houben

    (VIB Center for Brain and Disease Research
    KU Leuven)

  • Wouter Duverger

    (VIB Center for Brain and Disease Research
    KU Leuven)

  • Matthias Vleeschouwer

    (VIB Center for Brain and Disease Research
    KU Leuven)

  • Katerina Konstantoulea

    (VIB Center for Brain and Disease Research
    KU Leuven)

  • Fleur Nysen

    (VIB Center for Brain and Disease Research
    KU Leuven)

  • Thomas Schalck

    (Centre of Microbial and Plant Genetics;KU Leuven
    Center for Microbiology;VIB-KU Leuven)

  • Daniel J. Curwen

    (Monash University)

  • Lisandra L. Martin

    (Monash University)

  • Sebastien Carpentier

    (KULeuven)

  • Bernard Scorneaux

    (Aelin Therapeutics)

  • Jan Michiels

    (Centre of Microbial and Plant Genetics;KU Leuven
    Center for Microbiology;VIB-KU Leuven)

  • Joost Schymkowitz

    (VIB Center for Brain and Disease Research
    KU Leuven)

  • Frederic Rousseau

    (VIB Center for Brain and Disease Research
    KU Leuven)

Abstract

Drug-resistant bacteria pose an urgent global health threat, necessitating the development of antibacterial compounds with novel modes of action. Protein biosynthesis accounts for up to half of the energy expenditure of bacterial cells, and consequently inhibiting the efficiency or fidelity of the bacterial ribosome is a major target of existing antibiotics. Here, we describe an alternative mode of action that affects the same process: allowing translation to proceed but causing co-translational aggregation of the nascent peptidic chain. We show that treatment with an aggregation-prone peptide induces formation of polar inclusion bodies and activates the SsrA ribosome rescue pathway in bacteria. The inclusion bodies contain ribosomal proteins and ribosome hibernation factors, as well as mRNAs and cognate nascent chains of many proteins in amyloid-like structures, with a bias for membrane proteins with a fold rich in long-range beta-sheet interactions. The peptide is bactericidal against a wide range of pathogenic bacteria in planktonic growth and in biofilms, and reduces bacterial loads in mouse models of Escherichia coli and Acinetobacter baumannii infections. Our results indicate that disrupting protein homeostasis via co-translational aggregation constitutes a promising strategy for development of broad-spectrum antibacterials.

Suggested Citation

  • Laleh Khodaparast & Ladan Khodaparast & Ramon Duran-Romaña & Guiqin Wu & Bert Houben & Wouter Duverger & Matthias Vleeschouwer & Katerina Konstantoulea & Fleur Nysen & Thomas Schalck & Daniel J. Curwe, 2025. "Co-translational protein aggregation and ribosome stalling as a broad-spectrum antibacterial mechanism," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56873-z
    DOI: 10.1038/s41467-025-56873-z
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    References listed on IDEAS

    as
    1. Emiel Michiels & Kenny Roose & Rodrigo Gallardo & Ladan Khodaparast & Laleh Khodaparast & Rob van der Kant & Maxime Siemons & Bert Houben & Meine Ramakers & Hannah Wilkinson & Patricia Guerreiro & Nik, 2020. "Reverse engineering synthetic antiviral amyloids," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    2. Ladan Khodaparast & Laleh Khodaparast & Rodrigo Gallardo & Nikolaos N. Louros & Emiel Michiels & Reshmi Ramakrishnan & Meine Ramakers & Filip Claes & Lydia Young & Mohammad Shahrooei & Hannah Wilkinso, 2018. "Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    3. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    4. Ladan Khodaparast & Laleh Khodaparast & Guiqin Wu & Emiel Michiels & Rodrigo Gallardo & Bert Houben & Teresa Garcia & Matthias Vleeschouwer & Meine Ramakers & Hannah Wilkinson & Ramon Duran-Romaña & J, 2023. "Exploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Ashok Ganesan & Aleksandra Siekierska & Jacinte Beerten & Marijke Brams & Joost Van Durme & Greet De Baets & Rob Van der Kant & Rodrigo Gallardo & Meine Ramakers & Tobias Langenberg & Hannah Wilkinson, 2016. "Structural hot spots for the solubility of globular proteins," Nature Communications, Nature, vol. 7(1), pages 1-15, April.
    6. Toon Swings & David C. Marciano & Benu Atri & Rachel E. Bosserman & Chen Wang & Marlies Leysen & Camille Bonte & Thomas Schalck & Ian Furey & Bram Van den Bergh & Natalie Verstraeten & Peter J. Christ, 2018. "CRISPR-FRT targets shared sites in a knock-out collection for off-the-shelf genome editing," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
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