title: Tedizolid for the management of human infections: in vitro characteristics.
abstract: The emerging antibiotic resistance of Gram-positive pathogens represents a significant challenge to the management of human infections. The novel oxazolidinone tedizolid demonstrates antimicrobial activity across a broad range of Gram-positive pathogens and greater potency than linezolid against wild-type and drug-resistant pathogens, including linezolid-resistant Staphylococcus aureus strains possessing mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins L3 or L4. Strains harboring such mutations are also selected for much less frequently with tedizolid than with linezolid. In addition, tedizolid has a significant potency advantage over linezolid-resistant strains carrying the horizontally transferable cfr gene. Methylation of A2503 of 23S rRNA by the Cfr methyltransferase confers resistance to linezolid (and a variety of other 50S ribosomal subunit-targeted antibiotics) but not to tedizolid because of structural differences in A-ring C5 substituents between the 2 drugs. The greater potency and improved resistance profile of tedizolid provides the microbiologic basis for considering this molecule as an alternative to linezolid for the treatment of serious infections caused by Gram-positive pathogens.
authors.affiliation: Cubist Pharmaceuticals, San Diego, California.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Locke
authors.forename: Gary E
authors.initials: GE
authors.lastname: Zurenko
authors.forename: Karen Joy
authors.initials: KJ
authors.lastname: Shaw
authors.forename: Kenneth
authors.initials: K
authors.lastname: Bartizal
mesh_terms: D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial; D022761:Gene Transfer, Horizontal; D006801:Humans; D000069349:Linezolid; D010755:Organophosphates / Q000494:pharmacology* / Q000627:therapeutic use*; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D023303:Oxazolidinones / Q000494:pharmacology / Q000627:therapeutic use; D017354:Point Mutation; D012338:RNA, Ribosomal, 23S / Q000235:genetics / Q000378:metabolism; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins / Q000235:genetics; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D012359:tRNA Methyltransferases / Q000378:metabolism
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D010755:Organophosphates; D010080:Oxazoles; D023303:Oxazolidinones; D012338:RNA, Ribosomal, 23S; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins; C056368:ribosomal protein L4; D012359:tRNA Methyltransferases; D000069349:Linezolid; C515040:tedizolid phosphate
keywords: MRSA; cfr; oxazolidinone; resistance; tedizolid