Human serum triggers antibiotic tolerance in Staphylococcus aureus
File(s)s41467-022-29717-3.pdf (1.86 MB)
Published version
Author(s)
Ledger, E
Mesnage, S
Edwards, A
Type
Journal Article
Abstract
Staphylococcus aureus frequently causes infections that are challenging to treat, leading to high rates of persistent and relapsing infection. Here, to understand how the host environment influences treatment outcomes, we study the impact of human serum on staphylococcal antibiotic susceptibility. We show that serum triggers a high degree of tolerance to the lipopeptide antibiotic daptomycin and several other classes of antibiotic. Serum-induced daptomycin tolerance is due to two independent mechanisms. Firstly, the host defence peptide LL-37 induces tolerance by triggering the staphylococcal GraRS two-component system, leading to increased peptidoglycan accumulation. Secondly, GraRS-independent increases in membrane cardiolipin abundance are required for full tolerance. When both mechanisms are blocked, S. aureus incubated in serum is as susceptible to daptomycin as when grown in laboratory media. Our work demonstrates that host factors can significantly modulate antibiotic susceptibility via diverse mechanisms, and combination therapy may provide a way to mitigate this.
Date Issued
2022-04-19
Date Acceptance
2022-03-30
ISSN
2041-1723
Publisher
Nature Research
Start Page
1
End Page
19
Journal / Book Title
Nature Communications
Volume
13
Copyright Statement
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
License URI
Sponsor
Wellcome Trust
Identifier
https://www.nature.com/articles/s41467-022-29717-3
Grant Number
203812/Z/16/Z
Subjects
Anti-Bacterial Agents
Daptomycin
Humans
Microbial Sensitivity Tests
Staphylococcal Infections
Staphylococcus aureus
Humans
Staphylococcus aureus
Staphylococcal Infections
Daptomycin
Anti-Bacterial Agents
Microbial Sensitivity Tests
Publication Status
Published
Date Publish Online
2022-04-19