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Ca(2+)-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids

The lipopeptide daptomycin is used as an antibiotic to treat severe infections with gram-positive pathogens, such as methicillin resistant Staphylococcus aureus (MRSA) and drug-resistant enterococci. Its precise mechanism of action is incompletely understood, and a specific molecular target has not...

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Autores principales: Grein, Fabian, Müller, Anna, Scherer, Katharina M., Liu, Xinliang, Ludwig, Kevin C., Klöckner, Anna, Strach, Manuel, Sahl, Hans-Georg, Kubitscheck, Ulrich, Schneider, Tanja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081307/
https://www.ncbi.nlm.nih.gov/pubmed/32193379
http://dx.doi.org/10.1038/s41467-020-15257-1
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author Grein, Fabian
Müller, Anna
Scherer, Katharina M.
Liu, Xinliang
Ludwig, Kevin C.
Klöckner, Anna
Strach, Manuel
Sahl, Hans-Georg
Kubitscheck, Ulrich
Schneider, Tanja
author_facet Grein, Fabian
Müller, Anna
Scherer, Katharina M.
Liu, Xinliang
Ludwig, Kevin C.
Klöckner, Anna
Strach, Manuel
Sahl, Hans-Georg
Kubitscheck, Ulrich
Schneider, Tanja
author_sort Grein, Fabian
collection PubMed
description The lipopeptide daptomycin is used as an antibiotic to treat severe infections with gram-positive pathogens, such as methicillin resistant Staphylococcus aureus (MRSA) and drug-resistant enterococci. Its precise mechanism of action is incompletely understood, and a specific molecular target has not been identified. Here we show that Ca(2+)-daptomycin specifically interacts with undecaprenyl-coupled cell envelope precursors in the presence of the anionic phospholipid phosphatidylglycerol, forming a tripartite complex. We use microbiological and biochemical assays, in combination with fluorescence and optical sectioning microscopy of intact staphylococcal cells and model membrane systems. Binding primarily occurs at the staphylococcal septum and interrupts cell wall biosynthesis. This is followed by delocalisation of components of the peptidoglycan biosynthesis machinery and massive membrane rearrangements, which may account for the pleiotropic cellular events previously reported. The identification of carrier-bound cell wall precursors as specific targets explains the specificity of daptomycin for bacterial cells. Our work reconciles apparently inconsistent previous results, and supports a concise model for the mode of action of daptomycin.
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spelling pubmed-70813072020-03-23 Ca(2+)-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids Grein, Fabian Müller, Anna Scherer, Katharina M. Liu, Xinliang Ludwig, Kevin C. Klöckner, Anna Strach, Manuel Sahl, Hans-Georg Kubitscheck, Ulrich Schneider, Tanja Nat Commun Article The lipopeptide daptomycin is used as an antibiotic to treat severe infections with gram-positive pathogens, such as methicillin resistant Staphylococcus aureus (MRSA) and drug-resistant enterococci. Its precise mechanism of action is incompletely understood, and a specific molecular target has not been identified. Here we show that Ca(2+)-daptomycin specifically interacts with undecaprenyl-coupled cell envelope precursors in the presence of the anionic phospholipid phosphatidylglycerol, forming a tripartite complex. We use microbiological and biochemical assays, in combination with fluorescence and optical sectioning microscopy of intact staphylococcal cells and model membrane systems. Binding primarily occurs at the staphylococcal septum and interrupts cell wall biosynthesis. This is followed by delocalisation of components of the peptidoglycan biosynthesis machinery and massive membrane rearrangements, which may account for the pleiotropic cellular events previously reported. The identification of carrier-bound cell wall precursors as specific targets explains the specificity of daptomycin for bacterial cells. Our work reconciles apparently inconsistent previous results, and supports a concise model for the mode of action of daptomycin. Nature Publishing Group UK 2020-03-19 /pmc/articles/PMC7081307/ /pubmed/32193379 http://dx.doi.org/10.1038/s41467-020-15257-1 Text en © The Author(s) 2020 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Grein, Fabian
Müller, Anna
Scherer, Katharina M.
Liu, Xinliang
Ludwig, Kevin C.
Klöckner, Anna
Strach, Manuel
Sahl, Hans-Georg
Kubitscheck, Ulrich
Schneider, Tanja
Ca(2+)-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids
title Ca(2+)-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids
title_full Ca(2+)-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids
title_fullStr Ca(2+)-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids
title_full_unstemmed Ca(2+)-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids
title_short Ca(2+)-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids
title_sort ca(2+)-daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081307/
https://www.ncbi.nlm.nih.gov/pubmed/32193379
http://dx.doi.org/10.1038/s41467-020-15257-1
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