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The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S.
- Source :
-
MBio [mBio] 2018 Oct 09; Vol. 9 (5). Date of Electronic Publication: 2018 Oct 09. - Publication Year :
- 2018
-
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.<br /> (Copyright © 2018 Wenzel et al.)
- Subjects :
- Bacillus subtilis ultrastructure
Cell Membrane drug effects
Cell Wall drug effects
DNA Damage drug effects
DNA-Binding Proteins metabolism
Microbial Sensitivity Tests
Microscopy, Electron
Anti-Bacterial Agents pharmacology
Bacillus subtilis drug effects
Gramicidin pharmacology
Tyrocidine pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2150-7511
- Volume :
- 9
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- MBio
- Publication Type :
- Academic Journal
- Accession number :
- 30301848
- Full Text :
- https://doi.org/10.1128/mBio.00802-18