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Antimicrobial Agents and Chemotherapy, December 2008, p. 4442-4447, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00859-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of TR-700, the Antibacterial Moiety of the Prodrug TR-701, against Linezolid-Resistant Strains {triangledown}

K. J. Shaw,1* S. Poppe,2 R. Schaadt,2 V. Brown-Driver,1 J. Finn,1 C. M. Pillar,3 D. Shinabarger,2 and G. Zurenko2

Trius Therapeutics, Inc., San Diego, California,1 Micromyx, Kalamazoo, Michigan,2 Eurofins Medinet, Inc., Herndon, Virginia3

Received 27 June 2008/ Returned for modification 8 September 2008/ Accepted 28 September 2008

TR-701 is the orally active prodrug of TR-700, a novel oxazolidinone that demonstrates four- to eightfold-greater activity than linezolid (LZD) against Staphylococcus and Enterococcus spp. In this study evaluating the in vitro sensitivity of LZD-resistant isolates, TR-700 demonstrated 8- to 16-fold-greater potency than LZD against all strains tested, including methicillin-resistant Staphylococcus aureus (MRSA), strains of MRSA carrying the mobile cfr methyltransferase gene, and vancomycin-resistant enterococci. The MIC90 for TR-700 against LZD-resistant S. aureus was 2 µg/ml, demonstrating the utility of TR-700 against LZD-resistant strains. A model of TR-700 binding to 23S rRNA suggests that the increased potency of TR-700 is due to additional target site interactions and that TR-700 binding is less reliant on target residues associated with resistance to LZD.

* Corresponding author. Mailing address: Trius Therapeutics, Inc., 6310 Nancy Ridge Drive, Suite 105, San Diego, CA 92121. Phone: (858) 452-0370, ext. 225. Fax: (858) 452-0412. E-mail: kshaw{at}triusrx.com

{triangledown} Published ahead of print on 6 October 2008.

Antimicrobial Agents and Chemotherapy, December 2008, p. 4442-4447, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00859-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Locke, J. B., Hilgers, M., Shaw, K. J. (2009). Novel Ribosomal Mutations in Staphylococcus aureus Strains Identified through Selection with the Oxazolidinones Linezolid and Torezolid (TR-700). Antimicrob. Agents Chemother. 53: 5265-5274 [Abstract] [Full Text]  
  • Locke, J. B., Hilgers, M., Shaw, K. J. (2009). Mutations in Ribosomal Protein L3 Are Associated with Oxazolidinone Resistance in Staphylococci of Clinical Origin. Antimicrob. Agents Chemother. 53: 5275-5278 [Abstract] [Full Text]  
  • Lemaire, S., Van Bambeke, F., Appelbaum, P. C., Tulkens, P. M. (2009). Cellular pharmacokinetics and intracellular activity of torezolid (TR-700): studies with human macrophage (THP-1) and endothelial (HUVEC) cell lines. J Antimicrob Chemother 64: 1035-1043 [Abstract] [Full Text]  
  • Schaadt, R., Sweeney, D., Shinabarger, D., Zurenko, G. (2009). In Vitro Activity of TR-700, the Active Ingredient of the Antibacterial Prodrug TR-701, a Novel Oxazolidinone Antibacterial Agent. Antimicrob. Agents Chemother. 53: 3236-3239 [Abstract] [Full Text]  
  • Livermore, D. M., Mushtaq, S., Warner, M., Woodford, N. (2009). Activity of oxazolidinone TR-700 against linezolid-susceptible and -resistant staphylococci and enterococci. J Antimicrob Chemother 63: 713-715 [Abstract] [Full Text]  


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