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

eLife

Sebastian Kuhn¹  Christoph M Ernst¹  André Geyer¹  Bernhard Krismer²  Jessica Slavetinsky²  Janna N Hauser²  Cordula Gekeler²  Andreas Peschel²  Christoph J Slavetinsky³  Samuel Wagner⁴  Doris Heilingbrunner⁵  Michael Tesar⁵  Alexandra Kraus⁵ 

[1] Department of Infection Biology, Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), Eberhard Karls University Tübingen, Tübingen, Germany;German Centre for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany;Department of Infection Biology, Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), Eberhard Karls University Tübingen, Tübingen, Germany;German Centre for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany;Cluster of Excellence "Controlling Microbes to Fight Infections," University of Tübingen, Tübingen, Germany;Department of Infection Biology, Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), Eberhard Karls University Tübingen, Tübingen, Germany;Pediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany;German Centre for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany;Cluster of Excellence "Controlling Microbes to Fight Infections," University of Tübingen, Tübingen, Germany;Pediatric Surgery and Urology, University Children's Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany;German Centre for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany;Cluster of Excellence "Controlling Microbes to Fight Infections," University of Tübingen, Tübingen, Germany;Section of Cellular and Molecular Microbiology, Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, Germany;MorphoSys AG, Planegg, Germany;

关键词: Staphylococcus aureus;    MprF;    antivirulence drugs;    antimicrobial peptides;    MRSA;    bacterial lipids;    Other;   

DOI  :  10.7554/eLife.66376

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY