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Membrane depolarization kills dormant Bacillus subtilis cells by generating a lethal dose of ROS

Author

Listed:
  • Declan A. Gray

    (Newcastle University
    Centre for Antibiotic Resistance Research in Gothenburg (CARe)
    The Sahlgrenska Academy at the University of Gothenburg)

  • Biwen Wang

    (University of Amsterdam)

  • Margareth Sidarta

    (Centre for Antibiotic Resistance Research in Gothenburg (CARe)
    Chalmers University of Technology)

  • Fabián A. Cornejo

    (Max Planck Unit for the Science of Pathogens)

  • Jurian Wijnheijmer

    (University of Amsterdam)

  • Rupa Rani

    (Centre for Antibiotic Resistance Research in Gothenburg (CARe)
    Chalmers University of Technology)

  • Pamela Gamba

    (Newcastle University
    Keele Science Park)

  • Kürşad Turgay

    (Max Planck Unit for the Science of Pathogens
    Institut für Mikrobiologie)

  • Michaela Wenzel

    (Centre for Antibiotic Resistance Research in Gothenburg (CARe)
    Chalmers University of Technology)

  • Henrik Strahl

    (Newcastle University)

  • Leendert W. Hamoen

    (Newcastle University
    University of Amsterdam)

Abstract

The bactericidal activity of several antibiotics partially relies on the production of reactive oxygen species (ROS), which is generally linked to enhanced respiration and requires the Fenton reaction. Bacterial persister cells, an important cause of recurring infections, are tolerant to these antibiotics because they are in a dormant state. Here, we use Bacillus subtilis cells in stationary phase, as a model system of dormant cells, to show that pharmacological induction of membrane depolarization enhances the antibiotics’ bactericidal activity and also leads to ROS production. However, in contrast to previous studies, this results primarily in production of superoxide radicals and does not require the Fenton reaction. Genetic analyzes indicate that Rieske factor QcrA, the iron-sulfur subunit of respiratory complex III, seems to be a primary source of superoxide radicals. Interestingly, the membrane distribution of QcrA changes upon membrane depolarization, suggesting a dissociation of complex III. Thus, our data reveal an alternative mechanism by which antibiotics can cause lethal ROS levels, and may partially explain why membrane-targeting antibiotics are effective in eliminating persisters.

Suggested Citation

  • Declan A. Gray & Biwen Wang & Margareth Sidarta & Fabián A. Cornejo & Jurian Wijnheijmer & Rupa Rani & Pamela Gamba & Kürşad Turgay & Michaela Wenzel & Henrik Strahl & Leendert W. Hamoen, 2024. "Membrane depolarization kills dormant Bacillus subtilis cells by generating a lethal dose of ROS," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51347-0
    DOI: 10.1038/s41467-024-51347-0
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    References listed on IDEAS

    as
    1. Henrik Strahl & Frank Bürmann & Leendert W. Hamoen, 2014. "The actin homologue MreB organizes the bacterial cell membrane," Nature Communications, Nature, vol. 5(1), pages 1-11, May.
    2. Mehmet A. Orman & Mark P. Brynildsen, 2015. "Inhibition of stationary phase respiration impairs persister formation in E. coli," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    3. Declan A. Gray & Gaurav Dugar & Pamela Gamba & Henrik Strahl & Martijs J. Jonker & Leendert W. Hamoen, 2019. "Extreme slow growth as alternative strategy to survive deep starvation in bacteria," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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