Format

Send to

Choose Destination
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.

Author information

1
Bacterial Cell Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands m.wenzel@uva.nl l.w.hamoen@uva.nl.
2
Department of Medical Microbiology and Infection Control, Amsterdam University Medical Centers, Location VUMC, Amsterdam, The Netherlands.
3
BIOPEP Peptide Group, Department of Biochemistry, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa.
4
Bacterial Cell Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
5
Chemistry Institute UMR7177, University of Strasbourg/CNRS, Strasbourg, France.
6
Department of Physiology, Laboratory for Membrane Physiology and Technology, University of Freiburg, Freiburg, Germany.

Abstract

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.

KEYWORDS:

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

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center