Antibiotic-induced accumulation of lipid II synergizes with antimicrobial fatty acids to eradicate bacterial populations

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

The following data sets were generated

Article and author information

Author details

  1. Ashelyn E Sidders

    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8700-261X
  2. Katarzyna M Kedziora

    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  3. Melina Arts

    Institute for Pharmaceutical Microbiology, University of Bonn, Bonn, Germany
    Competing interests
    No competing interests declared.
  4. Jan-Martin Daniel

    Institute for Pharmaceutical Microbiology, University of Bonn, Bonn, Germany
    Competing interests
    No competing interests declared.
  5. Stefania de Benedetti

    Institute for Pharmaceutical Microbiology, University of Bonn, Bonn, Germany
    Competing interests
    No competing interests declared.
  6. Jenna E Beam

    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  7. Duyen T Bui

    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  8. Joshua B Parsons

    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  9. Tanja Schneider

    Institute for Pharmaceutical Microbiology, University of Bonn, Bonn, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7269-4716
  10. Sarah E Rowe

    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    Sarah E Rowe, is co-inventor on a provisional patent (WO2019018594A1) describing the use of membrane acting agents for potentiating antibiotic efficacy.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8955-359X
  11. Brian P Conlon

    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    bconlon@med.unc.edu
    Competing interests
    Brian P Conlon, is co-inventor on a provisional patent (WO2019018594A1) describing the use of membrane acting agents for potentiating antibiotic efficacy.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2155-8375

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

  1. Sophie Helaine, Harvard Medical School, United States

Version history

  1. Preprint posted: May 3, 2022 (view preprint)
  2. Received: May 13, 2022
  3. Accepted: March 5, 2023
  4. Accepted Manuscript published: March 6, 2023 (version 1)
  5. 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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  1. Ashelyn E Sidders
  2. Katarzyna M Kedziora
  3. Melina Arts
  4. Jan-Martin Daniel
  5. Stefania de Benedetti
  6. Jenna E Beam
  7. Duyen T Bui
  8. Joshua B Parsons
  9. Tanja Schneider
  10. Sarah E Rowe
  11. Brian P Conlon
(2023)
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

Share this article

https://doi.org/10.7554/eLife.80246

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