title: Structure-activity relationships of diverse oxazolidinones for linezolid-resistant Staphylococcus aureus strains possessing the cfr methyltransferase gene or ribosomal mutations.
abstract: Staphylococcal resistance to linezolid (LZD) is mediated through ribosomal mutations (23S rRNA or ribosomal proteins L3 and L4) or through methylation of 23S rRNA by the horizontally transferred Cfr methyltransferase. To investigate the structural basis for oxazolidinone activity against LZD-resistant (LZD(r)) strains, we compared structurally diverse, clinically relevant oxazolidinones, including LZD, radezolid (RX-1741), TR-700 (torezolid), and a set of TR-700 analogs (including novel CD-rings and various A-ring C-5 substituents), against a panel of laboratory-derived and clinical LZD(r) Staphylococcus aureus strains possessing a variety of resistance mechanisms. Potency against all strains was correlated with optimization of C- and D-rings, which interact with more highly conserved regions of the peptidyl transferase center binding site. Activity against cfr strains was retained with either hydroxymethyl or 1,2,3-triazole C-5 groups but was reduced by 2- to 8-fold in compounds with acetamide substituents. LZD, which possesses a C-5 acetamide group and lacks a D-ring substituent, demonstrated the lowest potency against all strains tested, particularly against cfr strains. These data reveal key features contributing to oxazolidinone activity and highlight structural tradeoffs between potency against susceptible strains and potency against strains with various resistance mechanisms.
authors.affiliation: Trius Therapeutics, Inc., 6310 Nancy Ridge Drive, Suite 101, San Diego, CA 92121, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Locke
authors.forename: John
authors.initials: J
authors.lastname: Finn
authors.forename: Mark
authors.initials: M
authors.lastname: Hilgers
authors.forename: Gracia
authors.initials: G
authors.lastname: Morales
authors.forename: Shahad
authors.initials: S
authors.lastname: Rahawi
authors.forename: Kedar
authors.initials: K
authors.lastname: G C
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Picazo
authors.forename: Weonbin
authors.initials: W
authors.lastname: Im
authors.forename: Karen Joy
authors.initials: KJ
authors.lastname: Shaw
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Stein
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics*; D000069349:Linezolid; D008780:Methyltransferases / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D023303:Oxazolidinones / Q000494:pharmacology*; D012270:Ribosomes / Q000235:genetics*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D023303:Oxazolidinones; D008780:Methyltransferases; D000069349:Linezolid