1. Microbiology and Infectious Disease
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Factors essential for L,D-transpeptidase-mediated peptidoglycan cross-linking and β-lactam resistance in Escherichia coli

  1. Jean-Emmanuel Hugonnet
  2. Dominique Mengin-Lecreulx
  3. Alejandro Monton
  4. Tanneke den Blaauwen
  5. Etienne Carbonnelle
  6. Carole Veckerlé
  7. Yves Brun
  8. Michael van Nieuwenhze
  9. Christiane Bouchier
  10. Kuyek Tu
  11. Louis B Rice
  12. Michel Arthur  Is a corresponding author
  1. INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, France
  2. Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-Saclay, France
  3. University of Amsterdam, Netherlands
  4. Indiana University, United States
  5. Institut Pasteur, France
  6. Brown University, United States
Research Article
  • Cited 71
  • Views 3,323
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Cite this article as: eLife 2016;5:e19469 doi: 10.7554/eLife.19469

Abstract

The target of β-lactam antibiotics is the D,D-transpeptidase activity of penicillin-binding proteins (PBPs) for synthesis of 4→3 cross-links in the peptidoglycan of bacterial cell walls. Unusual 3→3 cross-links formed by L,D-transpeptidases were first detected in Escherichia coli more than four decades ago, however no phenotype has previously been associated with their synthesis. Here we show that production of the L,D-transpeptidase YcbB in combination with elevated synthesis of the (p)ppGpp alarmone by RelA lead to full bypass of the D,D-transpeptidase activity of PBPs and to broad-spectrum β-lactam resistance. Production of YcbB was therefore sufficient to switch the role of (p)ppGpp from antibiotic tolerance to high-level β-lactam resistance. This observation identifies a new mode of peptidoglycan polymerization in E. coli that relies on an unexpectedly small number of enzyme activities comprising the glycosyltransferase activity of class A PBP1b and the D,D-carboxypeptidase activity of DacA in addition to the L,D-transpeptidase activity of YcbB.

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Author details

  1. Jean-Emmanuel Hugonnet

    INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  2. Dominique Mengin-Lecreulx

    Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France
    Competing interests
    The authors declare that no competing interests exist.

  3. Alejandro Monton

    Bacterial Cell Biology and Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  4. Tanneke den Blaauwen

    Bacterial Cell Biology and Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  5. Etienne Carbonnelle

    INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  6. Carole Veckerlé

    INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  7. Yves Brun

    Indiana University, Indiana, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Michael van Nieuwenhze

    Indiana University, Indiana, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Christiane Bouchier

    Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  10. Kuyek Tu

    INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  11. Louis B Rice

    Rhode Island Hospital, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Michel Arthur

    INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
    For correspondence
    michel.arthur@crc.jussieu.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1007-636X

Funding

National Institute of Allergy and Infectious Diseases (RO1 307 AI046626)

  • Louis B Rice
  • Michel Arthur

Joint Program Initiative on Antimicrobial Research (ZonMW project 60-60900-98-207)

  • Alejandro Monton

Joint Program Initiative on Antimicrobial Research (NAPCLI)

  • Jean-Emmanuel Hugonnet
  • Alejandro Monton
  • Tanneke den Blaauwen
  • Michel Arthur

National Institutes of Health (GM113172)

  • Michael van Nieuwenhze

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Michael S Gilmore, Harvard Medical School, United States

Publication history

  1. Received: July 8, 2016
  2. Accepted: October 20, 2016
  3. Accepted Manuscript published: October 21, 2016 (version 1)
  4. Version of Record published: November 1, 2016 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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