The last resort antibiotic daptomycin exhibits two independent antibacterial mechanisms of action

Jessica A. Buttress, Ann-Britt Schäfer, Alan Koh, Jessica Wheatley, Katarzyna Mickiewicz, Michaela Wenzel and Henrik Strahl ()
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Jessica A. Buttress: Newcastle University, Centre for Bacterial Cell Biology, Biosciences Institute, Faculty of Medical Sciences
Ann-Britt Schäfer: Chalmers University of Technology, Division of Chemical Biology, Department of Life Sciences
Alan Koh: Newcastle University, Centre for Bacterial Cell Biology, Biosciences Institute, Faculty of Medical Sciences
Jessica Wheatley: Newcastle University, Centre for Bacterial Cell Biology, Biosciences Institute, Faculty of Medical Sciences
Katarzyna Mickiewicz: Newcastle University, Centre for Bacterial Cell Biology, Biosciences Institute, Faculty of Medical Sciences
Michaela Wenzel: Chalmers University of Technology, Division of Chemical Biology, Department of Life Sciences
Henrik Strahl: Newcastle University, Centre for Bacterial Cell Biology, Biosciences Institute, Faculty of Medical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Daptomycin is a lipopeptide antibiotic, commonly used as last resort treatment against multidrug resistant Gram-positive pathogens. Despite its clinical success, the mechanism through which daptomycin exerts its antibacterial properties has remained controversial. Much of the debate is focused around daptomycin’s ability to depolarise the cytoplasmic membrane, potential formation of large membrane pores, and its more recently discovered capability to inhibit cell wall synthesis and disturb membrane lipid domain organisation through interactions with cell wall precursor lipids. Here we show that, rather than representing different facets of a single underlying activity, daptomycin exhibits two independent antibacterial mechanisms of action: (i) targeting of cell wall precursor lipids that leads to cell wall synthesis inhibition and (ii) membrane depolarisation that does not rely on interactions with cell wall precursor lipids. This dual mechanism of action provides an explanation for the frequently disagreeing findings obtained through in vivo and in vitro studies and explains why resistance development towards daptomycin is slow and multifactorial. In a broader context, this demonstrates that dual mechanism antibiotics can be clinically successful and exhibit favourable characteristics in terms of real-world, clinically relevant resistance development.

Date: 2025
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DOI: 10.1038/s41467-025-65287-w

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