1. Biochemistry and Chemical Biology
  2. Microbiology and Infectious Disease
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A cytoplasmic peptidoglycan amidase homologue controls mycobacterial cell wall synthesis

  1. Cara C Boutte
  2. Christina E Baer
  3. Kadamba Papavinasasundaram
  4. Weiru Liu
  5. Michael R Chase
  6. Xavier Meniche
  7. Sarah M Fortune
  8. Christopher M Sassetti
  9. Thomas R Ioerger
  10. Eric J Rubin  Is a corresponding author
  1. Harvard T.H. Chan School of Public Health, United States
  2. University of Massachusetts Medical School, United States
  3. Texas A&M University, United States
  4. Harvard TH Chan School of Public Health, United States
Research Article
  • Cited 40
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Cite this article as: eLife 2016;5:e14590 doi: 10.7554/eLife.14590

Abstract

Regulation of cell wall assembly is essential for bacterial survival and contributes to pathogenesis and antibiotic tolerance in Mycobacterium tuberculosis (Mtb). However, little is known about how the cell wall is regulated in stress. We found that CwlM, a protein homologous to peptidoglycan amidases, coordinates peptidoglycan synthesis with nutrient availability. Surprisingly, CwlM is sequestered from peptidoglycan (PG) by localization in the cytoplasm, and its enzymatic function is not essential. Rather, CwlM is phosphorylated and associates with MurA, the first enzyme in PG precursor synthesis. Phosphorylated CwlM activates MurA ~30 fold. CwlM is dephosphorylated in starvation, resulting in lower MurA activity, decreased cell wall metabolism, and increased tolerance to multiple antibiotics. A phylogenetic analysis of cwlM implies that localization in the cytoplasm drove the evolution of this factor. We describe a system that controls cell wall metabolism in response to starvation, and show that this regulation contributes to antibiotic tolerance.

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Author details

  1. Cara C Boutte

    Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Christina E Baer

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kadamba Papavinasasundaram

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Weiru Liu

    Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael R Chase

    Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xavier Meniche

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sarah M Fortune

    Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Christopher M Sassetti

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Thomas R Ioerger

    Department of Computer Science, Texas A&M University, College Station, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Eric J Rubin

    Department of Immunology and Infectious Disease, Harvard TH Chan School of Public Health, Boston, United States
    For correspondence
    erubin@hsph.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Michael Laub, Massachusetts Institute of Technology, United States

Publication history

  1. Received: January 21, 2016
  2. Accepted: June 14, 2016
  3. Accepted Manuscript published: June 15, 2016 (version 1)
  4. Version of Record published: July 15, 2016 (version 2)

Copyright

© 2016, Boutte 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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