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

eLife

Jessica Slavetinsky¹  Sebastian Kuhn¹  Samuel Wagner¹  Andreas Peschel²  Bernhard Krismer²  Doris Heilingbrunner²  Cordula Gekeler²  Janna N Hauser³  André Geyer⁴  Christoph M Ernst⁵  Michael Tesar⁵  Christoph J Slavetinsky⁵  Alexandra Kraus⁵ 

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

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

DOI  :  10.7554/eLife.66376

来源: DOAJ

【 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】

Unknown