title: Biochemical characterization of the interactions of the novel pleuromutilin derivative retapamulin with bacterial ribosomes.
abstract: Retapamulin is a semisynthetic pleuromutilin derivative being developed as a topical antibiotic for treating bacterial infections of the skin. It is potent in vitro against susceptible and multidrug-resistant organisms commonly associated with bacterial skin infections. We report detailed mode of action studies demonstrating that retapamulin binds to the bacterial ribosome with high affinity, inhibits ribosomal peptidyl transferase activity, and partially inhibits the binding of the initiator tRNA substrate to the ribosomal P-site. Taken together, these data distinguish the mode of action of retapamulin from that of other classes of antibiotics. This unique mode of action may explain the lack of clinically relevant, target-specific cross-resistance of retapamulin with antibacterials in current use.
authors.affiliation: GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA. kang.2.yan@gsk.com
authors.forename: Kang
authors.initials: K
authors.lastname: Yan
authors.forename: Lenore
authors.initials: L
authors.lastname: Madden
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Choudhry
authors.forename: Christine S
authors.initials: CS
authors.lastname: Voigt
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Richard R
authors.initials: RR
authors.lastname: Gontarek
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005456:Fluorescent Dyes; D008024:Ligands; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D011083:Polycyclic Compounds; D014176:Protein Biosynthesis; D011691:Puromycin / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012335:RNA, Ribosomal / Q000378:metabolism; D011817:Rabbits; D012156:Reticulocytes / Q000187:drug effects / Q000648:ultrastructure; D012270:Ribosomes / Q000187:drug effects*; D000097567:Pleuromutilins
chemical_list: D000900:Anti-Bacterial Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004224:Diterpenes; D005456:Fluorescent Dyes; D008024:Ligands; D008156:Luciferases; D011083:Polycyclic Compounds; D011691:Puromycin; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D000097567:Pleuromutilins; C508887:retapamulin