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Sequence selectivity of macrolide-induced translational attenuation.

Amber R Davis1, David W Gohara1, Mee-Ngan F Yap2

  • 1Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104.

Proceedings of the National Academy of Sciences of the United States of America
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Macrolide antibiotics like azithromycin do not stall bacterial protein synthesis at a fixed point. Instead, they cause specific ribosome stalling at diverse sites rich in proline and charged residues.

Keywords:
Staphylococcus aureusantibioticribosome stalling

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Area of Science:

  • Microbiology
  • Molecular Biology
  • Antibiotic Resistance

Background:

  • The "plug-in-the-bottle" model posits macrolide antibiotics halt bacterial translation universally after 6-8 amino acids.
  • This model suggests indiscriminate inhibition within the ribosome tunnel.

Purpose of the Study:

  • To investigate the precise mechanism of macrolide-induced translation inhibition in Staphylococcus aureus.
  • To challenge the prevailing "plug-in-the-bottle" model of macrolide action.

Main Methods:

  • Genome-wide analysis of translation.
  • Treatment of Staphylococcus aureus with azithromycin.
  • Identification and characterization of ribosome stalling sites.

Main Results:

  • Macrolides do not induce preferential ribosome stalling near the 5' end of mRNAs.
  • Specific stalling sites are scattered throughout coding regions, enriched in prolines and charged residues.
  • Structurally similar macrolides exhibit varying stalling efficiencies.

Conclusions:

  • Ribosome stalling by macrolides is not indiscriminate but occurs at specific motifs.
  • Stalling efficiency depends on arrest-inducing residues and the presence of the macrolide inducer.
  • The "plug-in-the-bottle" model is an oversimplification of macrolide antibiotic action.