The slow dissociation rate of K-1602 contributes to the enhanced inhibitory activity of this novel alkyl–aryl-bearing fluoroketolide |
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| Authors: | Marios Krokidis Anthony Bougas Maria Stavropoulou Dimitrios Kalpaxis |
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| Institution: | 1. Department of Pharmacology, Medical School, University of Athens, Athens, Greece,;2. Laboratory of Biochemistry, School of Medicine, University of Patras, Patras, Greece, and;3. Department of Chemistry, Technical University of Munich, Munich, Germany |
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| 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?×?104?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. |
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| Keywords: | Antibiotics antibiotic resistance macrolides ribosomes slow binding inhibitors |
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