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Antimicrobial Agents and Chemotherapy, April 2002, p. 1080-1085, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.1080-1085.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Oxazolidinone Antibiotics Target the P Site on Escherichia coli Ribosomes

Hiroyuki Aoki,¹ Lizhu Ke,¹ Susan M. Poppe,² Toni J. Poel,³ Elizabeth A. Weaver,³ Robert C. Gadwood,³ Richard C. Thomas,³ Dean L. Shinabarger,² and M. Clelia Ganoza^1,*

Banting and Best Department of Medical Research, Toronto, Ontario M5G 1L6, Canada,¹ Infectious Diseases Research,² Medicinal Chemistry, Pharmacia and Upjohn, Kalamazoo, Michigan 49001-0199³

Received 30 April 2001/ Returned for modification 20 September 2001/ Accepted 18 January 2002

The oxazolidinones are a novel class of antimicrobial agents that target protein synthesis in a wide spectrum of gram-positive and anaerobic bacteria. The oxazolidinone PNU-100766 (linezolid) inhibits the binding of fMet-tRNA to 70S ribosomes. Mutations to oxazolidinone resistance in Halobacterium halobium, Staphylococcus aureus, and Escherichia coli map at or near domain V of the 23S rRNA, suggesting that the oxazolidinones may target the peptidyl transferase region responsible for binding fMet-tRNA. This study demonstrates that the potency of oxazolidinones corresponds to increased inhibition of fMet-tRNA binding. The inhibition of fMet-tRNA binding is competitive with respect to the fMet-tRNA concentration, suggesting that the P site is affected. The fMet-tRNA reacts with puromycin to form peptide bonds in the presence of elongation factor P (EF-P), which is needed for optimum specificity and efficiency of peptide bond synthesis. Oxazolidinone inhibition of the P site was evaluated by first binding fMet-tRNA to the A site, followed by translocation to the P site with EF-G. All three of the oxazolidinones used in this study inhibited translocation of fMet-tRNA. We propose that the oxazolidinones target the ribosomal P site and pleiotropically affect fMet-tRNA binding, EF-P stimulated synthesis of peptide bonds, and, most markedly, EF-G-mediated translocation of fMet-tRNA into the P site.

M.C.G. dedicates this work to the memory of Clelia H. Finney.

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