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Lateral membrane organization as target of an antimicrobial peptidomimetic compound

Antimicrobial resistance is one of the leading concerns in medical care. Here we study the mechanism of action of an antimicrobial cationic tripeptide, AMC-109, by combining high speed-atomic force microscopy, molecular dynamics, fluorescence assays, and lipidomic analysis. We show that AMC-109 acti...

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Autores principales: Melcrová, Adéla, Maity, Sourav, Melcr, Josef, de Kok, Niels A. W., Gabler, Mariella, van der Eyden, Jonne, Stensen, Wenche, Svendsen, John S. M., Driessen, Arnold J. M., Marrink, Siewert J., Roos, Wouter H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10328936/
https://www.ncbi.nlm.nih.gov/pubmed/37419980
http://dx.doi.org/10.1038/s41467-023-39726-5
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author Melcrová, Adéla
Maity, Sourav
Melcr, Josef
de Kok, Niels A. W.
Gabler, Mariella
van der Eyden, Jonne
Stensen, Wenche
Svendsen, John S. M.
Driessen, Arnold J. M.
Marrink, Siewert J.
Roos, Wouter H.
author_facet Melcrová, Adéla
Maity, Sourav
Melcr, Josef
de Kok, Niels A. W.
Gabler, Mariella
van der Eyden, Jonne
Stensen, Wenche
Svendsen, John S. M.
Driessen, Arnold J. M.
Marrink, Siewert J.
Roos, Wouter H.
author_sort Melcrová, Adéla
collection PubMed
description Antimicrobial resistance is one of the leading concerns in medical care. Here we study the mechanism of action of an antimicrobial cationic tripeptide, AMC-109, by combining high speed-atomic force microscopy, molecular dynamics, fluorescence assays, and lipidomic analysis. We show that AMC-109 activity on negatively charged membranes derived from Staphylococcus aureus consists of two crucial steps. First, AMC-109 self-assembles into stable aggregates consisting of a hydrophobic core and a cationic surface, with specificity for negatively charged membranes. Second, upon incorporation into the membrane, individual peptides insert into the outer monolayer, affecting lateral membrane organization and dissolving membrane nanodomains, without forming pores. We propose that membrane domain dissolution triggered by AMC-109 may affect crucial functions such as protein sorting and cell wall synthesis. Our results indicate that the AMC-109 mode of action resembles that of the disinfectant benzalkonium chloride (BAK), but with enhanced selectivity for bacterial membranes.
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spelling pubmed-103289362023-07-09 Lateral membrane organization as target of an antimicrobial peptidomimetic compound Melcrová, Adéla Maity, Sourav Melcr, Josef de Kok, Niels A. W. Gabler, Mariella van der Eyden, Jonne Stensen, Wenche Svendsen, John S. M. Driessen, Arnold J. M. Marrink, Siewert J. Roos, Wouter H. Nat Commun Article Antimicrobial resistance is one of the leading concerns in medical care. Here we study the mechanism of action of an antimicrobial cationic tripeptide, AMC-109, by combining high speed-atomic force microscopy, molecular dynamics, fluorescence assays, and lipidomic analysis. We show that AMC-109 activity on negatively charged membranes derived from Staphylococcus aureus consists of two crucial steps. First, AMC-109 self-assembles into stable aggregates consisting of a hydrophobic core and a cationic surface, with specificity for negatively charged membranes. Second, upon incorporation into the membrane, individual peptides insert into the outer monolayer, affecting lateral membrane organization and dissolving membrane nanodomains, without forming pores. We propose that membrane domain dissolution triggered by AMC-109 may affect crucial functions such as protein sorting and cell wall synthesis. Our results indicate that the AMC-109 mode of action resembles that of the disinfectant benzalkonium chloride (BAK), but with enhanced selectivity for bacterial membranes. Nature Publishing Group UK 2023-07-07 /pmc/articles/PMC10328936/ /pubmed/37419980 http://dx.doi.org/10.1038/s41467-023-39726-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Melcrová, Adéla
Maity, Sourav
Melcr, Josef
de Kok, Niels A. W.
Gabler, Mariella
van der Eyden, Jonne
Stensen, Wenche
Svendsen, John S. M.
Driessen, Arnold J. M.
Marrink, Siewert J.
Roos, Wouter H.
Lateral membrane organization as target of an antimicrobial peptidomimetic compound
title Lateral membrane organization as target of an antimicrobial peptidomimetic compound
title_full Lateral membrane organization as target of an antimicrobial peptidomimetic compound
title_fullStr Lateral membrane organization as target of an antimicrobial peptidomimetic compound
title_full_unstemmed Lateral membrane organization as target of an antimicrobial peptidomimetic compound
title_short Lateral membrane organization as target of an antimicrobial peptidomimetic compound
title_sort lateral membrane organization as target of an antimicrobial peptidomimetic compound
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10328936/
https://www.ncbi.nlm.nih.gov/pubmed/37419980
http://dx.doi.org/10.1038/s41467-023-39726-5
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