In vitro activity of TR-700, the antibacterial moiety of the prodrug TR-701, against linezolid-resistant strains.
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 MIC(90) for TR-700 against LZD-resistant S. aureus was 2 microg/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.
Trius Therapeutics, Inc., 6310 Nancy Ridge Drive, Suite 105, San Diego, CA 92121, USA. kshaw@triusrx.com
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Shaw
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Poppe
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Schaadt
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Brown-Driver
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Finn
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Pillar
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Shinabarger
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Zurenko
D000081:Acetamides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D024881:Drug Resistance, Bacterial; D016983:Enterococcus / Q000187:drug effects*; D006801:Humans; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests / Q000592:standards; D008958:Models, Molecular; D023303:Oxazolidinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects*
D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D011355:Prodrugs; D000069349:Linezolid