1. Microbiology and Infectious Disease
Download icon

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 58
  • Views 3,064
  • Annotations
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.

Article and author information

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.

Metrics

  • 3,064
    Page views
  • 822
    Downloads
  • 58
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

    1. Epidemiology and Global Health
    2. Microbiology and Infectious Disease

    Estimating SARS-CoV-2 seroprevalence and epidemiological parameters with uncertainty from serological surveys

    Daniel B Larremore et al.
    Research Article

    Establishing how many people have been infected by SARS-CoV-2 remains an urgent priority for controlling the COVID-19 pandemic. Serological tests that identify past infection can be used to estimate cumulative incidence, but the relative accuracy and robustness of various sampling strategies has been unclear. We developed a flexible framework that integrates uncertainty from test characteristics, sample size, and heterogeneity in seroprevalence across subpopulations to compare estimates from sampling schemes. Using the same framework and making the assumption that seropositivity indicates immune protection, we propagated estimates and uncertainty through dynamical models to assess uncertainty in the epidemiological parameters needed to evaluate public health interventions, and found that sampling schemes informed by demographics and contact networks outperform uniform sampling. The framework can be adapted to optimize serosurvey design given test characteristics and capacity, population demography, sampling strategy, and modeling approach, and can be tailored to support decision-making around introducing or removing interventions.

    1. Epidemiology and Global Health
    2. Microbiology and Infectious Disease

    Viral load and contact heterogeneity predict SARS-CoV-2 transmission and super-spreading events

    Ashish Goyal et al.
    Research Article Updated

    SARS-CoV-2 is difficult to contain because many transmissions occur during pre-symptomatic infection. Unlike influenza, most SARS-CoV-2-infected people do not transmit while a small percentage infect large numbers of people. We designed mathematical models which link observed viral loads with epidemiologic features of each virus, including distribution of transmissions attributed to each infected person and duration between symptom onset in the transmitter and secondarily infected person. We identify that people infected with SARS-CoV-2 or influenza can be highly contagious for less than 1 day, congruent with peak viral load. SARS-CoV-2 super-spreader events occur when an infected person is shedding at a very high viral load and has a high number of exposed contacts. The higher predisposition of SARS-CoV-2 toward super-spreading events cannot be attributed to additional weeks of shedding relative to influenza. Rather, a person infected with SARS-CoV-2 exposes more people within equivalent physical contact networks, likely due to aerosolization.

    1. Microbiology and Infectious Disease

    A mobile genetic element increases bacterial host fitness by manipulating development

    Joshua M Jones et al.
    Research Article

    Horizontal gene transfer is a major force in bacterial evolution. Mobile genetic elements are responsible for much of horizontal gene transfer and also carry beneficial cargo genes. Uncovering strategies used by mobile genetic elements to benefit host cells is crucial for understanding their stability and spread in populations. We describe a benefit that ICEBs1, an integrative and conjugative element of Bacillus subtilis, provides to its host cells. Activation of ICEBs1 conferred a frequency-dependent selective advantage to host cells during two different developmental processes: biofilm formation and sporulation. These benefits were due to inhibition of biofilm-associated gene expression and delayed sporulation by ICEBs1-containing cells, enabling them to exploit their neighbors and grow more prior to development. A single ICEBs1 gene, devI (formerly ydcO), was both necessary and sufficient for inhibition of development. Manipulation of host developmental programs allows ICEBs1 to increase host fitness, thereby increasing propagation of the element.