Antibiotic-induced accumulation of lipid II synergizes with antimicrobial fatty acids to eradicate bacterial populations
- University of North Carolina at Chapel Hill, United States
- University of Bonn, Germany
Abstract
Antibiotic tolerance and antibiotic resistance are the two major obstacles to the efficient and reliable treatment of bacterial infections. Identifying antibiotic adjuvants that sensitize resistant and tolerant bacteria to antibiotic killing may lead to the development of superior treatments with improved outcomes. Vancomycin, a lipid II inhibitor, is a frontline antibiotic for treating methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacterial infections. However, vancomycin use has led to the increasing prevalence of bacterial strains with reduced susceptibility to vancomycin. Here we show that unsaturated fatty acids (UFAs) act as potent vancomycin adjuvants to rapidly kill a range of Gram-positive bacteria, including vancomycin-tolerant and resistant populations. The synergistic bactericidal activity relies on the accumulation of membrane-bound cell wall intermediates that generate large fluid patches in the membrane leading to protein delocalization, aberrant septal formation, and loss of membrane integrity. Our findings provide a natural therapeutic option that enhances vancomycin activity against difficult-to-treat pathogens and the underlying mechanism may be further exploited to develop antimicrobials that target recalcitrant infection.
Data availability
The raw numerical data for figures 1, 2, 3, 5, and 8 are provided in Source Data files for each figure.The full analysis code for Figure 4 is available on Github while all raw imaging data and key processed steps were deposited in Zenodo repository
Article and author information
Author details
Funding
National Institutes of Health (R01AI137273)
- Brian P Conlon
Burroughs Wellcome Fund
- Brian P Conlon
Cystic Fibrosis Foundation
- Brian P Conlon
Deutsche Forschungsgemeinschaft
- Tanja Schneider
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Sophie Helaine, Harvard Medical School, United States
Version history
- Preprint posted: May 3, 2022 (view preprint)
- Received: May 13, 2022
- Accepted: March 5, 2023
- Accepted Manuscript published: March 6, 2023 (version 1)
- Version of Record published: March 21, 2023 (version 2)
Copyright
© 2023, Sidders et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Antibiotic-induced accumulation of lipid II synergizes with antimicrobial fatty acids to eradicate bacterial populations
eLife 12:e80246.
https://doi.org/10.7554/eLife.80246
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