title: Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions.
abstract: The oxazolidinones are a new class of synthetic antibiotics with good activity against gram-positive pathogenic bacteria. Experiments with a susceptible Escherichia coli strain, UC6782, demonstrated that in vivo protein synthesis was inhibited by both eperezolid (formerly U-100592) and linezolid (formerly U-100766). Both linezolid and eperezolid were potent inhibitors of cell-free transcription-translation in E. coli, exhibiting 50% inhibitory concentrations (IC50s) of 1.8 and 2.5 microM, respectively. The ability to demonstrate inhibition of in vitro translation directed by phage MS2 RNA was greatly dependent upon the amount of RNA added to the assay. For eperezolid, 128 microg of RNA per ml produced an IC50 of 50 microM whereas a concentration of 32 microg/ml yielded an IC50 of 20 microM. Investigating lower RNA template concentrations in linezolid inhibition experiments revealed that 32 and 8 microg of MS2 phage RNA per ml produced IC50s of 24 and 15 microM, respectively. This phenomenon was shared by the translation initiation inhibitor kasugamycin but not by streptomycin. Neither oxazolidinone inhibited the formation of N-formylmethionyl-tRNA, elongation, or termination reactions of bacterial translation. The oxazolidinones appear to inhibit bacterial translation at the initiation phase of protein synthesis.
authors.affiliation: Infectious Diseases Research, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001-0199, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Shinabarger
authors.forename: K R
authors.initials: KR
authors.lastname: Marotti
authors.forename: R W
authors.initials: RW
authors.lastname: Murray
authors.forename: A H
authors.initials: AH
authors.lastname: Lin
authors.forename: E P
authors.initials: EP
authors.lastname: Melchior
authors.forename: S M
authors.initials: SM
authors.lastname: Swaney
authors.forename: D S
authors.initials: DS
authors.lastname: Dunyak
authors.forename: W F
authors.initials: WF
authors.lastname: Demyan
authors.forename: J M
authors.initials: JM
authors.lastname: Buysse
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis; D003090:Coliphages; D003470:Culture Media; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D000069349:Linezolid; D008826:Microbial Sensitivity Tests; D009239:N-Formylmethionine / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D023303:Oxazolidinones; D011072:Poly U / Q000378:metabolism; D011132:Polyribosomes / Q000187:drug effects / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D003470:Culture Media; D010080:Oxazoles; D023303:Oxazolidinones; D011072:Poly U; D009239:N-Formylmethionine; C098011:eperezolid; D000069349:Linezolid