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

  1. Christoph Josef Slavetinsky  Is a corresponding author
  2. Janna Nadine Hauser
  3. Cordula Gekeler
  4. Jessica Slavetinsky
  5. André Geyer
  6. Alexandra Kraus
  7. Doris Heilingbrunner
  8. Samuel Wagner
  9. Michael Tesar
  10. Bernhard Krismer
  11. Sebastian Kuhn
  12. Christoph M Ernst  Is a corresponding author
  13. Andreas Peschel
  1. Eberhard Karls University Tübingen, Germany
  2. MorphoSys AG, Germany
  3. University of Tübingen, Germany
  4. 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

  1. Christoph Josef Slavetinsky

    Pediatric Gastroenterology and Hepatology, Eberhard Karls University Tübingen, Tübingen, Germany
    For correspondence
    christoph.slavetinsky@med.uni-tuebingen.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5576-5906
  2. Janna Nadine Hauser

    Department of Infection Biology, Eberhard Karls University Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
  3. Cordula Gekeler

    Department of Infection Biology, Eberhard Karls University Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
  4. Jessica Slavetinsky

    Department of Infection Biology, Eberhard Karls University Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
  5. André Geyer

    Department of Infection Biology, Eberhard Karls University Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
  6. Alexandra Kraus

    MorphoSys AG, Planegg, Germany
    Competing interests
    Alexandra Kraus, Antibodies disclosed in the manuscript are part of patent Anti-staphylococcal antibodies" (US9873733B2 / EP2935324B1).
  7. Doris Heilingbrunner

    MorphoSys AG, Planegg, Germany
    Competing interests
    No competing interests declared.
  8. Samuel Wagner

    Cluster of Excellence 'Controlling Microbes to Fight Infections', University of Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1808-3556
  9. Michael Tesar

    MorphoSys AG, Planegg, Germany
    Competing interests
    Michael Tesar, Antibodies disclosed in the manuscript are part of patent Anti-staphylococcal antibodies" (US9873733B2 / EP2935324B1).
  10. Bernhard Krismer

    Department of Infection Biology, Eberhard Karls University Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
  11. Sebastian Kuhn

    Department of Infection Biology, Eberhard Karls University Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
  12. Christoph M Ernst

    Department of Molecular Biology and Center for Computational and Integrative Biology, Broad Institute, Cambridge, United States
    For correspondence
    cmernst@broadinstitute.org
    Competing interests
    Christoph M Ernst, Antibodies disclosed in the manuscript are part of patent Anti-staphylococcal antibodies" (US9873733B2 / EP2935324B1).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5575-1325
  13. Andreas Peschel

    Department of Infection Biology, Eberhard Karls University Tübingen, Tuebingen, Germany
    Competing interests
    Andreas Peschel, Antibodies disclosed in the manuscript are part of patent Anti-staphylococcal antibodies" (US9873733B2 / EP2935324B1).

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.

Reviewing Editor

  1. María Mercedes Zambrano, CorpoGen, Colombia

Publication history

  1. Preprint posted: November 14, 2020 (view preprint)
  2. Received: January 8, 2021
  3. Accepted: January 18, 2022
  4. Accepted Manuscript published: January 19, 2022 (version 1)
  5. Version of Record published: February 1, 2022 (version 2)

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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  1. Christoph Josef Slavetinsky
  2. Janna Nadine Hauser
  3. Cordula Gekeler
  4. Jessica Slavetinsky
  5. André Geyer
  6. Alexandra Kraus
  7. Doris Heilingbrunner
  8. Samuel Wagner
  9. Michael Tesar
  10. Bernhard Krismer
  11. Sebastian Kuhn
  12. Christoph M Ernst
  13. Andreas Peschel
(2022)
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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