title: Sequence selectivity of macrolide-induced translational attenuation.
abstract: The prevailing "plug-in-the-bottle" model suggests that macrolide antibiotics inhibit translation by binding inside the ribosome tunnel and indiscriminately arresting the elongation of every nascent polypeptide after the synthesis of six to eight amino acids. To test this model, we performed a genome-wide analysis of translation in azithromycin-treated Staphylococcus aureus. In contrast to earlier predictions, we found that the macrolide does not preferentially induce ribosome stalling near the 5' end of mRNAs, but rather acts at specific stalling sites that are scattered throughout the entire coding region. These sites are highly enriched in prolines and charged residues and are strikingly similar to other ligand-independent ribosome stalling motifs. Interestingly, the addition of structurally related macrolides had dramatically different effects on stalling efficiency. Our data suggest that ribosome stalling can occur at a surprisingly large number of low-complexity motifs in a fashion that depends only on a few arrest-inducing residues and the presence of a small molecule inducer.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104.
authors.forename: Amber R
authors.initials: AR
authors.lastname: Davis
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104.
authors.forename: David W
authors.initials: DW
authors.lastname: Gohara
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104 myap1@slu.edu.
authors.forename: Mee-Ngan F
authors.initials: MN
authors.lastname: Yap
mesh_terms: D017963:Azithromycin / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology*; D016366:Open Reading Frames / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D012270:Ribosomes / Q000378:metabolism; D020539:Sequence Analysis, Protein; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D018942:Macrolides; D010455:Peptides; D017963:Azithromycin; D011392:Proline
keywords: Staphylococcus aureus; antibiotic; ribosome stalling