title: Visualizing the 16-membered ring macrolides tildipirosin and tilmicosin bound to their ribosomal site.
abstract: The veterinary antibiotic tildipirosin (20,23-dipiperidinyl-mycaminosyl-tylonolide, Zuprevo) was developed recently to treat bovine and swine respiratory tract infections caused by bacterial pathogens such as Pasteurella multocida. Tildipirosin is a derivative of the naturally occurring compound tylosin. Here, we define drug-target interactions by combining chemical footprinting with structure modeling and show that tildipirosin, tylosin, and an earlier tylosin derivative, tilmicosin (20-dimethylpiperidinyl-mycaminosyl-tylonolide, Micotil), bind to the same macrolide site within the large subunit of P. multocida and Escherichia coli ribosomes. The drugs nevertheless differ in how they occupy this site. Interactions of the two piperidine components, which are unique to tildipirosin, distinguish this drug from tylosin and tilmicosin. The 23-piperidine of tildipirosin contacts ribosomal residues on the tunnel wall while its 20-piperidine is oriented into the tunnel lumen and is positioned to interfere with the growing nascent peptide.
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Poehlsgaard
authors.forename: Niels M
authors.initials: NM
authors.lastname: Andersen
authors.forename: Ralf
authors.initials: R
authors.lastname: Warrass
authors.forename: Stephen
authors.initials: S
authors.lastname: Douthwaite
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry; D001665:Binding Sites; D004926:Escherichia coli / Q000378:metabolism; D018942:Macrolides / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D016979:Pasteurella multocida / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012335:RNA, Ribosomal / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry*; D015645:Tylosin / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C576258:20,23-dipiperidinyl-mycaminosyl-tylonolide; D000900:Anti-Bacterial Agents; D018942:Macrolides; D012335:RNA, Ribosomal; C052319:tilmicosin; D015645:Tylosin