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

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...

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Autores principales:	Michaela Wenzel, Marina Rautenbach, J. Arnold Vosloo, Tjalling Siersma, Christopher H. M. Aisenbrey, Ekaterina Zaitseva, Wikus E. Laubscher, Wilma van Rensburg, Jan C. Behrends, Burkhard Bechinger, Leendert W. Hamoen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	antibiotics antimicrobial peptides bacterial cell biology bacterial cytological profiling cell membranes mode of action Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d9271b17950c45d6963eeb7b57386a0e
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spelling	oai:doaj.org-article:d9271b17950c45d6963eeb7b57386a0e2021-11-15T15:58:21ZThe Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S10.1128/mBio.00802-182150-7511https://doaj.org/article/d9271b17950c45d6963eeb7b57386a0e2018-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00802-18https://doaj.org/toc/2150-7511ABSTRACT 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.Michaela WenzelMarina RautenbachJ. Arnold VoslooTjalling SiersmaChristopher H. M. AisenbreyEkaterina ZaitsevaWikus E. LaubscherWilma van RensburgJan C. BehrendsBurkhard BechingerLeendert W. HamoenAmerican Society for Microbiologyarticleantibioticsantimicrobial peptidesbacterial cell biologybacterial cytological profilingcell membranesmode of actionMicrobiologyQR1-502ENmBio, Vol 9, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	antibiotics antimicrobial peptides bacterial cell biology bacterial cytological profiling cell membranes mode of action Microbiology QR1-502
spellingShingle	antibiotics antimicrobial peptides bacterial cell biology bacterial cytological profiling cell membranes mode of action Microbiology QR1-502 Michaela Wenzel Marina Rautenbach J. Arnold Vosloo Tjalling Siersma Christopher H. M. Aisenbrey Ekaterina Zaitseva Wikus E. Laubscher Wilma van Rensburg Jan C. Behrends Burkhard Bechinger Leendert W. Hamoen The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S
description	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.
format	article
author	Michaela Wenzel Marina Rautenbach J. Arnold Vosloo Tjalling Siersma Christopher H. M. Aisenbrey Ekaterina Zaitseva Wikus E. Laubscher Wilma van Rensburg Jan C. Behrends Burkhard Bechinger Leendert W. Hamoen
author_facet	Michaela Wenzel Marina Rautenbach J. Arnold Vosloo Tjalling Siersma Christopher H. M. Aisenbrey Ekaterina Zaitseva Wikus E. Laubscher Wilma van Rensburg Jan C. Behrends Burkhard Bechinger Leendert W. Hamoen
author_sort	Michaela Wenzel
title	The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S
title_short	The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S
title_full	The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S
title_fullStr	The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S
title_full_unstemmed	The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S
title_sort	multifaceted antibacterial mechanisms of the pioneering peptide antibiotics tyrocidine and gramicidin s
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/d9271b17950c45d6963eeb7b57386a0e
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The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S

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