title: Evernimicin binds exclusively to the 50S ribosomal subunit and inhibits translation in cell-free systems derived from both gram-positive and gram-negative bacteria.
abstract: Evernimicin (SCH 27899) is a new antibiotic with activity against a wide spectrum of gram-positive bacteria and activity against some gram-negative bacteria. Previous metabolic labeling studies indicated that evernimicin specifically inhibited protein synthesis in Staphylococcus aureus. Using a susceptible Escherichia coli strain, we demonstrated that evernimicin also inhibited protein synthesis in E. coli. In cell-free translation assays with extracts from either E. coli or S. aureus, evernimicin had a 50% inhibitory concentration of approximately 125 nM. In contrast, cell-free systems derived from wheat germ and rabbit reticulocytes were inhibited only by very high levels of evernimicin. Evernimicin did not promote transcript misreading. [(14)C]evernimicin specifically bound to the 50S subunit from E. coli. Nonlinear regression analysis of binding data generated with 70S ribosomes from E. coli and S. aureus and 50S subunits from E. coli returned dissociation constants of 84, 86, and 160 nM, respectively. In binding experiments, performed in the presence of excess quantities of a selection of antibiotics known to bind to the 50S subunit, only the structurally similar drug avilamycin blocked binding of [(14)C]evernimicin to ribosomes.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. paul.nicholas@spcorp.com
authors.forename: P M
authors.initials: PM
authors.lastname: McNicholas
authors.forename: D J
authors.initials: DJ
authors.lastname: Najarian
authors.forename: P A
authors.initials: PA
authors.lastname: Mann
authors.forename: D
authors.initials: D
authors.lastname: Hesk
authors.forename: R S
authors.initials: RS
authors.lastname: Hare
authors.forename: K J
authors.initials: KJ
authors.lastname: Shaw
authors.forename: T A
authors.initials: TA
authors.lastname: Black
mesh_terms: D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D001667:Binding, Competitive / Q000187:drug effects; D002250:Carbon Radioisotopes; D002474:Cell-Free System; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects*; D011817:Rabbits; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002250:Carbon Radioisotopes; C001202:evernimicin