The protein synthesis inhibitors, oxazolidinones and chloramphenicol, cause extensive translational inaccuracy in vivo.
The oxazolidinone family is a new class of synthetic antibiotics that bind to the bacterial 50S ribosomal subunit. Two members of the family, linezolid and XA043, were examined for their effects on translational fidelity using a lacZ reporter gene in vivo. Both promoted highly significant frameshifting and nonsense suppression. Chloramphenicol, a peptidyl transferase inhibitor, affected translational fidelity in a similar fashion. Neither the oxazolidinones nor chloramphenicol stimulated misincorporation of amino acid residues at position 461 in the lacZ gene. In contrast, the aminoglycosides gentamicin and paromomycin, which interact with the decoding region of the 30S subunit, caused significant misincorporation but only modest increases in frameshifting or stop codon readthrough of the lacZ gene. We conclude that effects on translational fidelity may play a significant role in the mechanism of action of the oxazolidinones.
Thompson
Jill
J
Department of Molecular and Cellular Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
O'Connor
Michael
M
Mills
Jonathan A
JA
Dahlberg
Albert E
AE
D000081:Acetamides / Q000494:pharmacology; D000596:Amino Acids / Q000378:metabolism; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002701:Chloramphenicol / Q000494:pharmacology*; D018388:Codon, Terminator / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics*; D018965:Frameshifting, Ribosomal / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D007763:Lac Operon / Q000235:genetics; D000069349:Linezolid; D020125:Mutation, Missense / Q000235:genetics; D023303:Oxazolidinones / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*
D000081:Acetamides; D000596:Amino Acids; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D018388:Codon, Terminator; D023303:Oxazolidinones; D011500:Protein Synthesis Inhibitors; C466982:XA043 antibiotic; D002701:Chloramphenicol; D000069349:Linezolid