tildipirosin and tilmicosin

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.

Topics: Anti-Bacterial Agents; Binding Sites; Escherichia coli; Macrolides; Models, Chemical; Models, Molecular; Pasteurella multocida; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Ribosomes; RNA, Ribosomal; Tylosin

Tildipirosin is a 16-membered-ring macrolide developed to treat bacterial pathogens, including Mannheimia haemolytica and Pasteurella multocida, that cause respiratory tract infections in cattle and swine. Here we evaluated the efficacy of tildipirosin at inhibiting protein synthesis on the ribosome (50% inhibitory concentration [IC(50)], 0.23 ± 0.01 μM) and compared it with the established veterinary macrolides tylosin, tilmicosin, and tulathromycin. Mutation and methylation at key rRNA nucleotides revealed differences in the interactions of these macrolides within their common ribosomal binding site.

Topics: Anti-Bacterial Agents; Binding Sites; Disaccharides; Escherichia coli; Heterocyclic Compounds; Mannheimia haemolytica; Microbial Sensitivity Tests; Molecular Docking Simulation; Mutation; Nucleotides; Pasteurella multocida; Protein Biosynthesis; Ribosomes; RNA, Ribosomal; Subcellular Fractions; Transcription, Genetic; Tylosin; Veterinary Drugs