Discovery of a small molecule that inhibits bacterial ribosome biogenesis

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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.

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Jonathan M Stokes

McMaster University, Hamilton, Canada

Competing interests
The authors declare that no competing interests exist.
Joseph H Davis

The Scripps Research Institute, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Chand S Mangat

McMaster University, Hamilton, Canada

Competing interests
The authors declare that no competing interests exist.
James R Williamson

The Scripps Research Institute, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Eric D Brown

McMaster University, Hamilton, Canada

For correspondence
ebrown@mcmaster.ca

Competing interests
The authors declare that no competing interests exist.

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