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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 Ganoza1,{dagger}*

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.

* Corresponding author. Mailing address: Banting and Best Department of Medical Research, 112 College St., Toronto, Ontario M5G 1L6, Canada. Phone: (416) 978-8918. Fax: (416) 978-8528. E-mail: m.ganoza{at}utoronto.ca.

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

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.



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