Cis-acting resistance peptides reveal dual ribosome inhibitory action of the macrolide josamycin
2009 (English)In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 91, no 8, 989-995 p.Article in journal (Refereed) Published
Macrolide antibiotics block the entrance of nascent peptides to the peptide exit tunnel of the large ribosomal subunit. Expression of specific cis-acting peptides confers low-level macrolide-resistance. We show that, in the case of josamycin, peptide expression does not eject josamycin from the ribosome, implying a peptide resistance mechanism different from that previously suggested for erythromycin. We find dipeptide formation and dipeptidyl-tRNA drop-off in the presence of josamycin to be much slower during translation of resistance than of control mRNAs. We demonstrate low-level josamycin resistance by over-expression of peptidyl-tRNA hydrolase. These findings suggest dual growth-inhibitory action of josamycin by (i) direct inhibition of peptide-elongation and (ii) indirect inhibition of peptide-elongation through rapid peptidyl-tRNA drop-off, leading to depletion of tRNA isoacceptors available for protein synthesis. We propose that josamycin resistance peptide expression brings ribosomes into a "quarantine" state with small drop-off rate, thereby eliminating the josamycin dependent depletion of tRNA isoacceptors in the protein-synthesis-active state.
Place, publisher, year, edition, pages
2009. Vol. 91, no 8, 989-995 p.
Macrolide, Josamycin, Protein synthesis, Inhibition, Resistance
Research subject Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-104046DOI: 10.1016/j.biochi.2009.05.002ISI: 000268530700006PubMedID: 19463886OAI: oai:DiVA.org:uu-104046DiVA: diva2:219295