Discovery of a small molecule that inhibits bacterial ribosome biogenesis
Jonathan M Stokes,
Joseph H Davis,
Chand S Mangat,
James R Williamson,
Eric D Brown
Affiliations
Jonathan M Stokes
Michael G DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada
Joseph H Davis
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States; Department of Chemistry, The Scripps Research Institute, La Jolla, United States; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States
Chand S Mangat
Michael G DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada
James R Williamson
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States; Department of Chemistry, The Scripps Research Institute, La Jolla, United States; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States
Eric D Brown
Michael G DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada
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°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.
