On the mechanism of action of 9-O-arylalkyloxime derivatives of 6-Omycaminosyltylonolide, a new class of 16-membered macrolide antibiotics. Mol Pharmacol. 2006; 70:1271–1280. [PubMed: 16873579

New 16-membered 9-aryl-alkyl oxime derivatives of 5-O-my-caminosyl-tylonolid (OMT) have recently been prepared and were found to exhibit high activity against macrolide-resistant strains. In this study, we show that these compounds do not affect the binding of tRNAs to ribosomes in a cell-free system derived from Escherichia coli and that they cannot inhibit pep-tidyltransferase, peptidyl-tRNA translocation, or poly(U)-depen-dent poly(Phe) synthesis. However, they severely inhibit poly(A)-dependent poly(Lys) synthesis and compete with eryth-romycin or tylosin for binding to common or partially overlap-ping sites in the ribosome. According to footprinting analysis, the lactone ring of these compounds seems to occupy the classic binding site of macrolides that is located at the entrance of the exit tunnel, whereas the extending alkyl-aryl side chai