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Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF

The pandemic of antibiotic resistance represents a major human health threat demanding new antimicrobial strategies. Multiple peptide resistance factor (MprF) is the synthase and flippase of the phospholipid lysyl-phosphatidylglycerol that increases virulence and resistance of methicillin-resistant...

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Autores principales: Slavetinsky, Christoph J, Hauser, Janna N, Gekeler, Cordula, Slavetinsky, Jessica, Geyer, André, Kraus, Alexandra, Heilingbrunner, Doris, Wagner, Samuel, Tesar, Michael, Krismer, Bernhard, Kuhn, Sebastian, Ernst, Christoph M, Peschel, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8806190/
https://www.ncbi.nlm.nih.gov/pubmed/35044295
http://dx.doi.org/10.7554/eLife.66376
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author Slavetinsky, Christoph J
Hauser, Janna N
Gekeler, Cordula
Slavetinsky, Jessica
Geyer, André
Kraus, Alexandra
Heilingbrunner, Doris
Wagner, Samuel
Tesar, Michael
Krismer, Bernhard
Kuhn, Sebastian
Ernst, Christoph M
Peschel, Andreas
author_facet Slavetinsky, Christoph J
Hauser, Janna N
Gekeler, Cordula
Slavetinsky, Jessica
Geyer, André
Kraus, Alexandra
Heilingbrunner, Doris
Wagner, Samuel
Tesar, Michael
Krismer, Bernhard
Kuhn, Sebastian
Ernst, Christoph M
Peschel, Andreas
author_sort Slavetinsky, Christoph J
collection PubMed
description The pandemic of antibiotic resistance represents a major human health threat demanding new antimicrobial strategies. Multiple peptide resistance factor (MprF) is the synthase and flippase of the phospholipid lysyl-phosphatidylglycerol that increases virulence and resistance of methicillin-resistant Staphylococcus aureus (MRSA) and other pathogens to cationic host defense peptides and antibiotics. With the aim to design MprF inhibitors that could sensitize MRSA to antimicrobial agents and support the clearance of staphylococcal infections with minimal selection pressure, we developed MprF-targeting monoclonal antibodies, which bound and blocked the MprF flippase subunit. Antibody M-C7.1 targeted a specific loop in the flippase domain that proved to be exposed at both sides of the bacterial membrane, thereby enhancing the mechanistic understanding of bacterial lipid translocation. M-C7.1 rendered MRSA susceptible to host antimicrobial peptides and antibiotics such as daptomycin, and it impaired MRSA survival in human phagocytes. Thus, MprF inhibitors are recommended for new antivirulence approaches against MRSA and other bacterial pathogens.
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spelling pubmed-88061902022-02-02 Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF Slavetinsky, Christoph J Hauser, Janna N Gekeler, Cordula Slavetinsky, Jessica Geyer, André Kraus, Alexandra Heilingbrunner, Doris Wagner, Samuel Tesar, Michael Krismer, Bernhard Kuhn, Sebastian Ernst, Christoph M Peschel, Andreas eLife Microbiology and Infectious Disease The pandemic of antibiotic resistance represents a major human health threat demanding new antimicrobial strategies. Multiple peptide resistance factor (MprF) is the synthase and flippase of the phospholipid lysyl-phosphatidylglycerol that increases virulence and resistance of methicillin-resistant Staphylococcus aureus (MRSA) and other pathogens to cationic host defense peptides and antibiotics. With the aim to design MprF inhibitors that could sensitize MRSA to antimicrobial agents and support the clearance of staphylococcal infections with minimal selection pressure, we developed MprF-targeting monoclonal antibodies, which bound and blocked the MprF flippase subunit. Antibody M-C7.1 targeted a specific loop in the flippase domain that proved to be exposed at both sides of the bacterial membrane, thereby enhancing the mechanistic understanding of bacterial lipid translocation. M-C7.1 rendered MRSA susceptible to host antimicrobial peptides and antibiotics such as daptomycin, and it impaired MRSA survival in human phagocytes. Thus, MprF inhibitors are recommended for new antivirulence approaches against MRSA and other bacterial pathogens. eLife Sciences Publications, Ltd 2022-01-19 /pmc/articles/PMC8806190/ /pubmed/35044295 http://dx.doi.org/10.7554/eLife.66376 Text en © 2022, Slavetinsky et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Microbiology and Infectious Disease
Slavetinsky, Christoph J
Hauser, Janna N
Gekeler, Cordula
Slavetinsky, Jessica
Geyer, André
Kraus, Alexandra
Heilingbrunner, Doris
Wagner, Samuel
Tesar, Michael
Krismer, Bernhard
Kuhn, Sebastian
Ernst, Christoph M
Peschel, Andreas
Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF
title Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF
title_full Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF
title_fullStr Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF
title_full_unstemmed Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF
title_short Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF
title_sort sensitizing staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase mprf
topic Microbiology and Infectious Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8806190/
https://www.ncbi.nlm.nih.gov/pubmed/35044295
http://dx.doi.org/10.7554/eLife.66376
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