CozE is a member of the MreCD complex that directs cell elongation in Streptococcus pneumoniae

  • Nature Microbiology 2, Article number: 16237 (2016)
  • doi:10.1038/nmicrobiol.2016.237
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Most bacterial cells are surrounded by a peptidoglycan cell wall that is essential for their integrity. The major synthases of this exoskeleton are called penicillin-binding proteins (PBPs)1,2. Surprisingly little is known about how cells control these enzymes, given their importance as drug targets. In the model Gram-negative bacterium Escherichia coli, outer membrane lipoproteins are critical activators of the class A PBPs (aPBPs)3,4, bifunctional synthases capable of polymerizing and crosslinking peptidoglycan to build the exoskeletal matrix1. Regulators of PBP activity in Gram-positive bacteria have yet to be discovered but are likely to be distinct due to the absence of an outer membrane. To uncover Gram-positive PBP regulatory factors, we used transposon-sequencing (Tn-Seq)5 to screen for mutations affecting the growth of Streptococcus pneumoniae cells when the aPBP synthase PBP1a was inactivated. Our analysis revealed a set of genes that were essential for growth in wild-type cells yet dispensable when pbp1a was deleted. The proteins encoded by these genes include the conserved cell wall elongation factors MreC and MreD2,6,7, as well as a membrane protein of unknown function (SPD_0768) that we have named CozE (coordinator of zonal elongation). Our results indicate that CozE is a member of the MreCD complex of S. pneumoniae that directs the activity of PBP1a to the midcell plane where it promotes zonal cell elongation and normal morphology. CozE homologues are broadly distributed among bacteria, suggesting that they represent a widespread family of morphogenic proteins controlling cell wall biogenesis by the PBPs.

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Change history

  • Corrected online 14 July 2017

    In the PDF version of this article previously published, the year of publication provided in the footer of each page and in the 'How to cite' section was erroneously given as 2017, it should have been 2016. This error has now been corrected. The HTML version of the article was not affected.


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The authors thank all members of the Bernhardt and Rudner laboratories for support and comments. A. Fenton was a jointly mentored postdoctoral fellow bridging work in both laboratories. The authors thank R. Yunck, H. Kimsey, M. Winkler, T. van Opijnen, A. Camilli, N. Campo, J.-W. Veening, T. Vernet and D. Morrison for strains, reagents and technical assistance. This work was supported by the National Institutes of Health (R01AI083365 to T.G.B., CETR U19 AI109764 to T.G.B. and D.Z.R., GM073831 to D.Z.R. and RC2 GM092616 to D.Z.R.).

Author information


  1. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Andrew K. Fenton
    • , Lamya El Mortaji
    • , Derek T. C. Lau
    • , David Z. Rudner
    •  & Thomas G. Bernhardt


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A.K.F. performed all experiments, designed part of the experimental programme and co-authored the manuscript. L.E.M. carried out essential pilot experiments for the project. D.T.C.L. helped adopt the Tn-seq data analysis pipeline and proofread the manuscript. D.Z.R. and T.G.B. co-supervised the project and co-authored the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to David Z. Rudner or Thomas G. Bernhardt.

Supplementary information

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    Supplementary information

    Supplementary Figures 1-17; Supplementary Tables 1-4; Supplementary References

Excel files

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    Supplementary Table 5

    Raw Tn-seq analysis data for wt vs pbp1a