Visualizing the 16-Membered Ring Macrolides Tildipirosin and Tilmicosin Bound to Their Ribosomal Site

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.