Membrane depolarization kills dormant Bacillus subtilis cells by generating a lethal dose of ROS
Journal article, 2024
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.
Author
Declan Alan Gray
Centre for Antibiotic Resistance Research in Gothenburg (CARe)
University of Gothenburg
Newcastle University
Biwen Wang
Swammerdam Institute for Life Sciences
Margareth Sidarta
Chalmers, Life Sciences, Chemical Biology
Centre for Antibiotic Resistance Research in Gothenburg (CARe)
Fabián A. Cornejo
Max Planck Unit for the Science of Pathogens
Jurian Wijnheijmer
Swammerdam Institute for Life Sciences
Rupa Rani
Centre for Antibiotic Resistance Research in Gothenburg (CARe)
Chalmers, Life Sciences, Chemical Biology
Pamela Gamba
Newcastle University
Charles River UK Ltd.
K. Turgay
Max Planck Unit for the Science of Pathogens
University of Hanover
Michaela Wenzel
Chalmers, Life Sciences, Chemical Biology
Centre for Antibiotic Resistance Research in Gothenburg (CARe)
Henrik Strahl
Newcastle University
Leendert W. Hamoen
Swammerdam Institute for Life Sciences
Newcastle University
Nature Communications
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 15 1 6877Antibiotic-induced amino acid release - A new antimicrobial strategy?
Swedish Research Council (VR) (2019-04521), 2020-01-01 -- 2023-12-31.
Subject Categories
Microbiology
Microbiology in the medical area
DOI
10.1038/s41467-024-51347-0
PubMed
39128925