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

Autor:	Grein F; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany.; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany., Müller A; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany., Scherer KM; Institute for Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany., Liu X; Institute for Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany., Ludwig KC; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany., Klöckner A; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany.; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany., Strach M; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany., Sahl HG; Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, University of Bonn, Bonn, Germany., Kubitscheck U; Institute for Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany. u.kubitscheck@uni-bonn.de., Schneider T; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany. tschneider@uni-bonn.de.; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany. tschneider@uni-bonn.de.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Mar 19; Vol. 11 (1), pp. 1455. Date of Electronic Publication: 2020 Mar 19.
DOI:	10.1038/s41467-020-15257-1
Abstrakt:	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.
Databáze:	MEDLINE
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