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 × 10⁴M⁻¹ s⁻¹ and a dissociation rate constant equal to 0.0025 min⁻¹. Both constants contribute to produce an overall inhibition constant K_i equal to 1.49 × 10⁻⁸M, which correlates very well with the superior activity of this compound when compared with many other ketolides or fluoroketolides.

• Antibiotics
• antibiotic resistance
• macrolides
• ribosomes
• slow binding inhibitors

Acknowledgements

We thank Kosan Biosciences Inc. for providing the new ketolide K-1602 and Dr Daniel Wilson for critical reading of the manuscript. This work was partially supported by the Research Committee of Patras University, program “K. Karatheodori” (grant C.573 to G.P.D.), and the IKYDA program for short-term fellowship to M.K. and M.S.

Declaration of interest

The authors report no conflicts of interest.