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Human serum triggers antibiotic tolerance in Staphylococcus aureus

Author

Listed:
  • Elizabeth V. K. Ledger

    (Imperial College London)

  • Stéphane Mesnage

    (University of Sheffield)

  • Andrew M. Edwards

    (Imperial College London)

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.

Suggested Citation

  • Elizabeth V. K. Ledger & Stéphane Mesnage & Andrew M. Edwards, 2022. "Human serum triggers antibiotic tolerance in Staphylococcus aureus," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29717-3
    DOI: 10.1038/s41467-022-29717-3
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    References listed on IDEAS

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    1. Fabian Grein & Anna Müller & Katharina M. Scherer & Xinliang Liu & Kevin C. Ludwig & Anna Klöckner & Manuel Strach & Hans-Georg Sahl & Ulrich Kubitscheck & Tanja Schneider, 2020. "Ca2+-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    2. Frédéric Peyrusson & Hugo Varet & Tiep Khac Nguyen & Rachel Legendre & Odile Sismeiro & Jean-Yves Coppée & Christiane Wolz & Tanel Tenson & Françoise Van Bambeke, 2020. "Intracellular Staphylococcus aureus persisters upon antibiotic exposure," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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