title: The general mode of translation inhibition by macrolide antibiotics.
abstract: Macrolides are clinically important antibiotics thought to inhibit bacterial growth by impeding the passage of newly synthesized polypeptides through the nascent peptide exit tunnel of the bacterial ribosome. Recent data challenged this view by showing that macrolide antibiotics can differentially affect synthesis of individual proteins. To understand the general mechanism of macrolide action, we used genome-wide ribosome profiling and analyzed the redistribution of ribosomes translating highly expressed genes in bacterial cells treated with high concentrations of macrolide antibiotics. The metagene analysis indicated that inhibition of early rounds of translation, which would be characteristic of the conventional view of macrolide action, occurs only at a limited number of genes. Translation of most genes proceeds past the 5'-proximal codons and can be arrested at more distal codons when the ribosome encounters specific short sequence motifs. The problematic sequence motifs are confined to the nascent peptide residues in the peptidyl transferase center but not to the peptide segment that contacts the antibiotic molecule in the exit tunnel. Therefore, it appears that the general mode of macrolide action involves selective inhibition of peptide bond formation between specific combinations of donor and acceptor substrates. Additional factors operating in the living cell but not functioning during in vitro protein synthesis may modulate site-specific action of macrolide antibiotics.
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607;
authors.forename: Krishna
authors.initials: K
authors.lastname: Kannan
authors.affiliation: Center for Research Informatics (CRI), Research Resources Center, University of Illinois, Chicago, IL 60612;
authors.forename: Pinal
authors.initials: P
authors.lastname: Kanabar
authors.affiliation: Institute of Technology, University of Tartu, 50411 Tartu, Estonia;
authors.forename: David
authors.initials: D
authors.lastname: Schryer
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607; Institute of Biochemistry and Biology, University of Potsdam, D-14424 Potsdam, Germany; and.
authors.forename: Tanja
authors.initials: T
authors.lastname: Florin
authors.affiliation: Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, and California Institute for Quantitative Biosciences, University of California, San Francisco, CA 94158.
authors.forename: Eugene
authors.initials: E
authors.lastname: Oh
authors.affiliation: Center for Research Informatics (CRI), Research Resources Center, University of Illinois, Chicago, IL 60612;
authors.forename: Neil
authors.initials: N
authors.lastname: Bahroos
authors.affiliation: Institute of Technology, University of Tartu, 50411 Tartu, Estonia;
authors.forename: Tanel
authors.initials: T
authors.lastname: Tenson
authors.affiliation: Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, and California Institute for Quantitative Biosciences, University of California, San Francisco, CA 94158.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Weissman
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607; shura@uic.edu.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Mankin
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003062:Codon / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000096:biosynthesis* / Q000235:genetics; D055106:Genome-Wide Association Study; D018942:Macrolides / Q000494:pharmacology*; D014176:Protein Biosynthesis; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D003062:Codon; D029968:Escherichia coli Proteins; D018942:Macrolides
keywords: antibiotics; macrolides; peptidyl transferase; ribosome; translation