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Gatifloxacin is a recently marketed quinolone with an enhanced activity against gram-positive bacteria compared with that of ciprofloxacin (4, 12, 13, 18). The structural differences between gatifloxacin and ciprofloxacin are substituents at the C-8 position of the quinolone nucleus (gatifloxacin, C-8-methoxy; ciprofloxacin, C-8-H) and at the C-3′ position of the piperazinyl moiety of the C-7 position (gatifloxacin, C-3′-methyl; ciprofloxacin, C-3′-H). Several studies have directed attention to substituents at the C-8 position of the quinolone nucleus (1, 2, 5-10, 14, 15, 19, 20). Introduction of the methoxy group at the C-8 position was thought to ensure potent activity against gram-positive bacteria (2, 6, 9, 20). However, there have been few studies on the effect of C-8 substituents against type II topoisomerases. Thus, to investigate the effect of the C-8 and C-3′ substituents of gatifloxacin against type II topoisomerases in Staphylococcus aureus, the activities of the quinolones AM-1121 (C-8-H, C-3′-methyl) and AM-1147 (C-8-methoxy, C-3′-H), which are structurally related to gatifloxacin,​gatifloxacin, were compared with those of gatifloxacin and ciprofloxacin.    TABLE 1.  Target inhibition and antibacterial activity of gatifloxacin and its related compounds    The quinolones tested were synthesized in-house. The bacterial strain used in this study was the quinolone-susceptible clinical isolate S. aureus MS5935 (3). MICs were determined by using agar dilution methodology according to NCCLS guidelines (11).  The GyrA and GyrB subunits of DNA gyrase and the GrlA and GrlB subunits of topoisomerase IV of MS5935 were prepared by a method described previously (16, 17). The activities of each enzyme were determined by a method described previously (16, 17). The effects of the quinolones were evaluated based on the concentrations required to inhibit 50% of the enzyme reaction (IC50s).  The IC50s of C-8-methoxy compounds (gatifloxacin and AM-1147) against topoisomerase IV were almost equal to those of their C-8-H counterparts (AM-1121 and ciprofloxacin), whereas the inhibitory activities of C-8-methoxy compounds against DNA gyrase were about six times higher than those of their C-8-H counterparts (Table ​(Table1;1; Fig. ​Fig.1).1). The C-3′-methyl moiety had little effect on the inhibitory activity against both DNA gyrase and topoisomerase IV. These results indicate that introduction of the C-8-methoxy group to the quinolone ring enhances the inhibitory activity against DNA gyrase without exerting influence on topoisomerase IV inhibition.    FIG. 1.  Inhibitory activities of gatifloxacin and its related compounds against topoisomerase IV (A) and DNA gyrase (B).    The C-8-methoxy compounds showed two- to fourfold-lower MICs than their C-8-H counterparts. On the other hand, the antibacterial activities of C-3′-methyl compounds were similar or slightly superior to those of their C-3′-H counterparts. These results indicate that the C-8-methoxy group of these compounds has a greater effect on the increment of the activity against the wild-type strain, whereas the C-3′-methyl group is slightly involved in the increment of this activity.  It was previously reported that the inhibition of both target enzymes contributes to the antibacterial activities of quinolones because the antibacterial activities of most quinolones were decreased by both the grlA and gyrA mutations (17). Therefore, it is suggested that an increase in the inhibitory activity of the C-8-methoxy compounds against DNA gyrase is the possible mechanism underlying their potent antibacterial activity.  In summary, introduction of the methoxy group at the C-8position of the quinolone nucleus enhances inhibitory activity against DNA gyrase, leading to the potent activity of gatifloxacin against S. aureus.

Contribution of the C-8-Methoxy Group of Gatifloxacin to Inhibition of Type II Topoisomerases of Staphylococcus aureus