Peptide-mediated macrolide resistance reveals possible specific interactions in the nascent peptide exit tunnel

Expression of specific short peptides can render cells resistant to macrolide antibiotics. Peptides conferring resistance to structurally different macrolides including oleandomycin, azithromycin, azaerythromycin, josamycin and a ketolide cethromycin were selected from a random pentapeptide expression library. Analysis of the entire collection of the resistance peptides allowed their classification into five distinct groups according to their sequence similarity and the type of resistance they confer. A strong correlation was observed between the structures of macrolide antibiotics and sequences of the peptides conferring resistance. Such a correlation indicates that sequence-specific interactions between the nascent peptide and the macrolide antibiotic and/or the ribosome can occur in the ribosomal exit tunnel.