1. Biochemistry and Chemical Biology
  2. Microbiology and Infectious Disease
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Discovery of a small molecule that inhibits bacterial ribosome biogenesis

  1. Jonathan M Stokes
  2. Joseph H Davis
  3. Chand S Mangat
  4. James R Williamson
  5. Eric D Brown  Is a corresponding author
  1. McMaster University, Canada
  2. The Scripps Research Institute, United States
Research Article
  • Cited 37
  • Views 6,372
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Cite this article as: eLife 2014;3:e03574 doi: 10.7554/eLife.03574

Abstract

While small molecule inhibitors of the bacterial ribosome have been instrumental in understanding protein translation, no such probes exist to study ribosome biogenesis. We screened a diverse chemical collection that included previously approved drugs for compounds that induced cold sensitive growth inhibition in the model bacterium Escherichia coli. Among the most cold sensitive was lamotrigine, an anticonvulsant drug. Lamotrigine treatment resulted in the rapid accumulation of immature 30S and 50S ribosomal subunits at 15{degree sign}C. Importantly, this was not the result of translation inhibition, as lamotrigine was incapable of perturbing protein synthesis in vivo or in vitro. Spontaneous suppressor mutations blocking lamotrigine activity mapped solely to the poorly characterized domain II of translation initiation factor IF2, and prevented the binding of lamotrigine to IF2 in vitro. This work establishes lamotrigine as a widely available chemical probe of bacterial ribosome biogenesis and suggests a role for E. coli IF2 in ribosome assembly.

Article and author information

Author details

  1. Jonathan M Stokes

    McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Joseph H Davis

    The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Chand S Mangat

    McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. James R Williamson

    The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Eric D Brown

    McMaster University, Hamilton, Canada
    For correspondence
    ebrown@mcmaster.ca
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Roberto Kolter, Harvard Medical School, United States

Publication history

  1. Received: June 4, 2014
  2. Accepted: September 17, 2014
  3. Accepted Manuscript published: September 18, 2014 (version 1)
  4. Version of Record published: October 7, 2014 (version 2)

Copyright

© 2014, Stokes 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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