Visualizing the 16-membered ring macrolides tildipirosin and tilmicosin bound to their ribosomal site

Area of Science:

• Veterinary Pharmacology
• Molecular Biology
• Bacterial Ribosome Structure

Background:

• Tildipirosin is a veterinary antibiotic used for respiratory infections in cattle and swine.
• It is a derivative of tylosin, a naturally occurring macrolide antibiotic.
• Bacterial respiratory infections pose a significant challenge in livestock management.

Purpose of the Study:

• To elucidate the drug-target interactions of tildipirosin at the molecular level.
• To compare the binding of tildipirosin, tylosin, and tilmicosin to bacterial ribosomes.
• To understand the structural basis for tildipirosin's efficacy.

Main Methods:

• Chemical footprinting techniques were employed to map drug-binding sites.
• Structure modeling was used to visualize drug-ribosome interactions.
• Comparative analysis of macrolide antibiotic binding to P. multocida and E. coli ribosomes.

Main Results:

• Tildipirosin, tylosin, and tilmicosin bind to the identical macrolide site on the large ribosomal subunit.
• Tildipirosin's unique 20,23-dipiperidinyl structure dictates distinct interactions within the ribosome.
• The 23-piperidine group contacts the ribosomal tunnel wall, while the 20-piperidine group enters the tunnel lumen.

Conclusions:

• Tildipirosin's distinct binding mode, facilitated by its piperidine moieties, differentiates it from tylosin and tilmicosin.
• The positioning of tildipirosin's 20-piperidine group suggests a mechanism for inhibiting nascent peptide elongation.
• Understanding these molecular interactions can inform the development of novel antibiotics.