Kishii Ryuta, Takei Masaya, Fukuda Hideyuki, Hayashi Katsuhiko, Hosaka Masaki
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Shimotsuga, Tochigi 329-0114, Japan.
Antimicrob Agents Chemother. 2003 Jan;47(1):77-81. doi: 10.1128/AAC.47.1.77-81.2003.
The inhibitory activities (50% inhibitory concentrations [IC(50)s]) of gatifloxacin and other quinolones against both DNA gyrase and topoisomerase IV of the wild-type Streptococcus pneumoniae IID553 were determined. The IC(50)s of 10 compounds ranged from 4.28 to 582 microg/ml against DNA gyrase and from 1.90 to 35.2 microg/ml against topoisomerase IV. The inhibitory activity against DNA gyrase was more varied than that against topoisomerase IV among fluoroquinolones. The IC(50)s for DNA gyrase of the 8-methoxy quinolones gatifloxacin and AM-1147 were approximately seven times lower than those of their 8-H counterparts AM-1121 and ciprofloxacin, whereas the IC(50)s for topoisomerase IV were 1.5 times lower. Moreover, the IC(50) ratios (IC(50) for DNA gyrase/IC(50) for topoisomerase IV) of gatifloxacin, AM-1147, and moxifloxacin, which possess 8-methoxy groups, were almost the same. The 8-methoxy quinolones showed higher antibacterial activity and less mutant selectivity against IID553 than their 8-H counterparts. These results suggest that the 8-methoxy group enhances both target inhibition, especially for DNA gyrase, leading to potent antipneumococcal activity and dual inhibition against both DNA gyrase and topoisomerase IV in the bacterial cell.
测定了加替沙星和其他喹诺酮类药物对野生型肺炎链球菌IID553的DNA旋转酶和拓扑异构酶IV的抑制活性（50%抑制浓度[IC50]）。10种化合物对DNA旋转酶的IC50范围为4.28至582微克/毫升，对拓扑异构酶IV的IC50范围为1.90至35.2微克/毫升。在氟喹诺酮类药物中，对DNA旋转酶的抑制活性比对拓扑异构酶IV的抑制活性变化更大。8-甲氧基喹诺酮类药物加替沙星和AM-1147对DNA旋转酶的IC50约为其8-H对应物AM-1121和环丙沙星的七分之一，而对拓扑异构酶IV的IC50则低1.5倍。此外，具有8-甲氧基的加替沙星、AM-1147和莫西沙星的IC50比值（DNA旋转酶的IC50/拓扑异构酶IV的IC50）几乎相同。与它们的8-H对应物相比，8-甲氧基喹诺酮类药物对IID553表现出更高的抗菌活性和更低的突变选择性。这些结果表明，8-甲氧基基团增强了对靶点的抑制作用，尤其是对DNA旋转酶的抑制作用，从而导致强效的抗肺炎球菌活性以及对细菌细胞中的DNA旋转酶和拓扑异构酶IV的双重抑制作用。
