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Antimicrobial Agents and Chemotherapy, December 1998, p. 3251-3255, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Oxazolidinone Linezolid Inhibits Initiation of Protein Synthesis in Bacteria

Steve M. Swaney,1 Hiroyuki Aoki,2 M. Clelia Ganoza,2 and Dean L. Shinabarger1,*

Infectious Diseases Research, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001,1 and Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada M5G 1L62

Received 3 February 1998/Returned for modification 26 May 1998/Accepted 21 September 1998

The oxazolidinones represent a new class of antimicrobial agents which are active against multidrug-resistant staphylococci, streptococci, and enterococci. Previous studies have demonstrated that oxazolidinones inhibit bacterial translation in vitro at a step preceding elongation but after the charging of N-formylmethionine to the initiator tRNA molecule. The event that occurs between these two steps is termed initiation. Initiation of protein synthesis requires the simultaneous presence of N-formylmethionine-tRNA, the 30S ribosomal subunit, mRNA, GTP, and the initiation factors IF1, IF2, and IF3. An initiation complex assay measuring the binding of [3H]N-formylmethionyl-tRNA to ribosomes in response to mRNA binding was used in order to investigate the mechanism of oxazolidinone action. Linezolid inhibited initiation complex formation with either the 30S or the 70S ribosomal subunits from Escherichia coli. In addition, complex formation with Staphylococcus aureus 70S tight-couple ribosomes was inhibited by linezolid. Linezolid did not inhibit the independent binding of either mRNA or N-formylmethionyl-tRNA to E. coli 30S ribosomal subunits, nor did it prevent the formation of the IF2-N-formylmethionyl-tRNA binary complex. The results demonstrate that oxazolidinones inhibit the formation of the initiation complex in bacterial translation systems by preventing formation of the N-formylmethionyl-tRNA-ribosome-mRNA ternary complex.

* Corresponding author. Mailing address: Infectious Diseases Research, Pharmacia & Upjohn, Inc., 7000 Portage Rd., Kalamazoo, MI 49001-0199. Phone: (616) 833-9356. Fax: (616) 833-0992. E-mail: dlshinab{at}am.pnu.com.

Antimicrobial Agents and Chemotherapy, December 1998, p. 3251-3255, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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