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mBio. 2018 Oct 9;9(5). pii: e00802-18. doi: 10.1128/mBio.00802-18.

The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S.

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Bacterial Cell Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands
Department of Medical Microbiology and Infection Control, Amsterdam University Medical Centers, Location VUMC, Amsterdam, The Netherlands.
BIOPEP Peptide Group, Department of Biochemistry, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa.
Bacterial Cell Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
Chemistry Institute UMR7177, University of Strasbourg/CNRS, Strasbourg, France.
Department of Physiology, Laboratory for Membrane Physiology and Technology, University of Freiburg, Freiburg, Germany.


Cyclic β-sheet decapeptides from the tyrocidine group and the homologous gramicidin S were the first commercially used antibiotics, yet it remains unclear exactly how they kill bacteria. We investigated their mode of action using a bacterial cytological profiling approach. Tyrocidines form defined ion-conducting pores, induce lipid phase separation, and strongly reduce membrane fluidity, resulting in delocalization of a broad range of peripheral and integral membrane proteins. Interestingly, they also cause DNA damage and interfere with DNA-binding proteins. Despite sharing 50% sequence identity with tyrocidines, gramicidin S causes only mild lipid demixing with minor effects on membrane fluidity and permeability. Gramicidin S delocalizes peripheral membrane proteins involved in cell division and cell envelope synthesis but does not affect integral membrane proteins or DNA. Our results shed a new light on the multifaceted antibacterial mechanisms of these antibiotics and explain why resistance to them is virtually nonexistent.IMPORTANCE Cyclic β-sheet decapeptides, such as tyrocidines and gramicidin S, were among the first antibiotics in clinical application. Although they have been used for such a long time, there is virtually no resistance to them, which has led to a renewed interest in this peptide class. Both tyrocidines and gramicidin S are thought to disrupt the bacterial membrane. However, this knowledge is mainly derived from in vitro studies, and there is surprisingly little knowledge about how these long-established antibiotics kill bacteria. Our results shed new light on the antibacterial mechanism of β-sheet peptide antibiotics and explain why they are still so effective and why there is so little resistance to them.


antibiotics; antimicrobial peptides; bacterial cell biology; bacterial cytological profiling; cell membranes; mode of action

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