title: Distinct mode of interaction of a novel ketolide antibiotic that displays enhanced antimicrobial activity.
abstract: Ketolides represent the latest generation of macrolide antibiotics, displaying improved activities against some erythromycin-resistant strains, while maintaining their activity against erythromycin-susceptible ones. In this study, we present a new ketolide, K-1325, that carries an alkyl-aryl side chain at C-13 of the lactone ring. According to our genetic and biochemical studies, K-1325 binds within the nascent polypeptide exit tunnel, at a site previously described as the primary attachment site of all macrolide antibiotics. Compared with telithromycin, K-1325 displays enhanced antimicrobial activity against wild-type Escherichia coli strains, as well as against strains bearing the U2609C mutation in 23S rRNA. Chemical protection experiments showed that the alkyl-aryl side chain of K-1325 interacts specifically with helix 35 of 23S rRNA, a fact leading to an increased affinity of U2609C mutant ribosomes for the drug and rationalizing the enhanced effectiveness of this new ketolide.
authors.affiliation: Laboratory of Biochemistry, School of Medicine, University of Patras, Patras, Greece.
authors.forename: Ekaterini C
authors.initials: EC
authors.lastname: Kouvela
authors.forename: Dimitrios L
authors.initials: DL
authors.lastname: Kalpaxis
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Wilson
authors.forename: George P
authors.initials: GP
authors.lastname: Dinos
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004917:Erythromycin / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects*; D048628:Ketolides / Q000494:pharmacology*; D012338:RNA, Ribosomal, 23S / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D012338:RNA, Ribosomal, 23S; D004917:Erythromycin