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

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Autorschaft

  • 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

Organisationseinheiten

Externe Organisationen

  • Newcastle University
  • Centre for Antibiotic Resistance Research in Gothenburg (CARe)
  • Universiteit van Amsterdam (UvA)
  • Chalmers University of Technology
  • Max-Planck-Forschungsstelle für die Wissenschaft der Pathogene (MPUSP)
Forschungs-netzwerk anzeigen

Details

OriginalspracheEnglisch
Aufsatznummer6877
Seitenumfang13
FachzeitschriftNature Communications
Jahrgang15
Ausgabenummer1
Frühes Online-Datum11 Aug. 2024
PublikationsstatusVeröffentlicht - Dez. 2024

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.

ASJC Scopus Sachgebiete

Zitieren

Membrane depolarization kills dormant Bacillus subtilis cells by generating a lethal dose of ROS. / Gray, Declan A.; Wang, Biwen; Sidarta, Margareth et al.
in: Nature Communications, Jahrgang 15, Nr. 1, 6877, 12.2024.

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Gray, DA, Wang, B, Sidarta, M, Cornejo, FA, Wijnheijmer, J, Rani, R, Gamba, P, Turgay, K, Wenzel, M, Strahl, H & Hamoen, LW 2024, 'Membrane depolarization kills dormant Bacillus subtilis cells by generating a lethal dose of ROS', Nature Communications, Jg. 15, Nr. 1, 6877. https://doi.org/10.1038/s41467-024-51347-0
Gray, D. A., Wang, B., Sidarta, M., Cornejo, F. A., Wijnheijmer, J., Rani, R., Gamba, P., Turgay, K., Wenzel, M., Strahl, H., & Hamoen, L. W. (2024). Membrane depolarization kills dormant Bacillus subtilis cells by generating a lethal dose of ROS. Nature Communications, 15(1), Artikel 6877. https://doi.org/10.1038/s41467-024-51347-0
Gray DA, Wang B, Sidarta M, Cornejo FA, Wijnheijmer J, Rani R et al. Membrane depolarization kills dormant Bacillus subtilis cells by generating a lethal dose of ROS. Nature Communications. 2024 Dez;15(1):6877. Epub 2024 Aug 11. doi: 10.1038/s41467-024-51347-0
Gray, Declan A. ; Wang, Biwen ; Sidarta, Margareth et al. / Membrane depolarization kills dormant Bacillus subtilis cells by generating a lethal dose of ROS. in: Nature Communications. 2024 ; Jahrgang 15, Nr. 1.
Download
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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{\textquoteright} 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.",
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AU - Sidarta, Margareth

AU - Cornejo, Fabián A.

AU - Wijnheijmer, Jurian

AU - Rani, Rupa

AU - Gamba, Pamela

AU - Turgay, Kürşad

AU - Wenzel, Michaela

AU - Strahl, Henrik

AU - Hamoen, Leendert W.

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024/12

Y1 - 2024/12

N2 - 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.

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