Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF
- Eberhard Karls University Tübingen, Germany
- MorphoSys AG, Germany
- University of Tübingen, Germany
- Broad Institute, United States
Abstract
The pandemic of antibiotic resistance represents a major human health threat demanding new antimicrobial strategies. 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 anti-virulence approaches against MRSA and other bacterial pathogens.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Christoph Josef Slavetinsky
Funding
Deutsche Forschungsgemeinschaft (EXC-2124/1-09.001_0)
- Christoph Josef Slavetinsky
Deutsche Forschungsgemeinschaft (EXC-2124/1-09.010_0)
- Christoph Josef Slavetinsky
Deutsches Zentrum für Infektionsforschung (TTU 08.806)
- Christoph Josef Slavetinsky
Deutsches Zentrum für Infektionsforschung (TTU 08.806)
- Andreas Peschel
Deutsche Forschungsgemeinschaft (SFB 766/1-3,TP A08)
- Andreas Peschel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Slavetinsky et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF
eLife 11:e66376.
https://doi.org/10.7554/eLife.66376
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