Interaction of Quinolones Carrying New R1 Group with DNA Gyrase.

Leprosy is a chronic infectious disease caused by and the treatment of choice is ofloxacin (OFX). Specific amino acid substitutions in DNA gyrase of have been reported leading to resistance against the drug. In our previous study, WQ-3810, a fluoroquinolone with a new R1 group (6-amino-3,5-difluoropyridin-2-yl) was shown to have a strong inhibitory activity on OFX-resistant DNA gyrases of , and the structural characteristics of its R1 group was predicted to enhance the inhibitory activity. To further understand the contribution of the R1 group, WQ-3334 with the same R1 group as WQ-3810, WQ-4064, and WQ-4065, but with slightly modified R1 group, were assessed on their activities against recombinant DNA gyrase of . An study was conducted to understand the molecular interactions between DNA gyrase and WQ compounds. WQ-3334 and WQ-3810 were shown to have greater inhibitory activity against DNA gyrase than others. Furthermore, analysis using quinolone-resistant DNA gyrases showed that WQ-3334 had greater inhibitory activity than WQ-3810. The R8 group was shown to be a factor for the linkage of the R1 groups with GyrB by an study. The inhibitory effect of WQ compounds that have a new R1 group against DNA gyrase can be enhanced by improving the binding affinity with different R8 group molecules. The information obtained by this work could be applied to design new fluoroquinolones effective for quinolone-resistant and other bacterial pathogens.