title: The slow dissociation rate of K-1602 contributes to the enhanced inhibitory activity of this novel alkyl-aryl-bearing fluoroketolide.
abstract: Ketolides belong to the latest generation of macrolides and are not only effective against macrolide susceptible bacterial strains but also against some macrolide resistant strains. Here we present data providing insights into the mechanism of action of K-1602, a novel alkyl-aryl-bearing fluoroketolide. According to our data, the K-1602 interacts with the ribosome as a one-step slow binding inhibitor, displaying an association rate constant equal to 0.28 × 10(4) M(-1) s(-1) and a dissociation rate constant equal to 0.0025 min(-1). Both constants contribute to produce an overall inhibition constant Ki equal to 1.49 × 10(-8) M, which correlates very well with the superior activity of this compound when compared with many other ketolides or fluoroketolides.
authors: a Department of Pharmacology , Medical School, University of Athens , Athens , Greece .
authors: Marios
authors: M
authors: Krokidis
authors: b Laboratory of Biochemistry , School of Medicine, University of Patras , Patras , Greece , and.
authors: Anthony
authors: A
authors: Bougas
authors: c Department of Chemistry , Technical University of Munich , Munich , Germany.
authors: Maria
authors: M
authors: Stavropoulou
authors: b Laboratory of Biochemistry , School of Medicine, University of Patras , Patras , Greece , and.
authors: Dimitrios
authors: D
authors: Kalpaxis
authors: b Laboratory of Biochemistry , School of Medicine, University of Patras , Patras , Greece , and.
authors: George P
authors: GP
authors: Dinos
mesh_terms: D001667:Binding, Competitive; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D048628:Ketolides / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D011691:Puromycin / Q000737:chemistry; D012269:Ribosomal Proteins / Q000737:chemistry / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects*; D015645:Tylosin / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000624543:K-1602 ketolide; D048628:Ketolides; D012269:Ribosomal Proteins; D011691:Puromycin; D015645:Tylosin
keywords: Antibiotics; antibiotic resistance; macrolides; ribosomes; slow binding inhibitors