Takei M, Fukuda H, Kishii R, Hosaka M
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi, Shimotsuga, Tochigi 329-0114, Japan.
Antimicrob Agents Chemother. 2001 Dec;45(12):3544-7. doi: 10.1128/AAC.45.12.3544-3547.2001.
The antibacterial activities and target inhibition of 15 quinolones against grlA and gyrA mutant strains were studied. The strains were obtained from wild-type Staphylococcus aureus MS5935 by selection with norfloxacin and nadifloxacin, respectively. The antibacterial activities of most quinolones against both mutant strains were lower than those against the wild-type strain. The ratios of MICs for the gyrA mutant strain to those for the grlA mutant strain (MIC ratio) varied from 0.125 to 4. The ratios of 50% inhibitory concentrations (IC(50)s) of quinolones against topoisomerase IV to those against DNA gyrase (IC(50) ratios) also varied, from 0.177 to 5.52. A significant correlation between the MIC ratios and the IC(50) ratios was observed (r = 0.919; P < 0.001). These results suggest that the antibacterial activities of quinolones against the wild-type strain are involved not only in topoisomerase IV inhibition but also in DNA gyrase inhibition and that the target preference in the wild-type strain can be anticipated by the MIC ratios. Based on the MIC ratios, the quinolones were classified into three categories. Type I quinolones (norfloxacin, enoxacin, fleroxacin, ciprofloxacin, lomefloxacin, trovafloxacin, grepafloxacin, ofloxacin, and levofloxacin) had MIC ratios of <1, type II quinolones (sparfloxacin and nadifloxacin) had MIC ratios of >1, and type III quinolones (gatifloxacin, pazufloxacin, moxifloxacin, and clinafloxacin) had MIC ratios of 1. Type I and type II quinolones seem to prefer topoisomerase IV and DNA gyrase, respectively. Type III quinolones seem to target both enzymes at nearly the same level in bacterial cells (a phenomenon known as the dual-targeting property), and their IC(50) ratios were approximately 2.
研究了15种喹诺酮类药物对grlA和gyrA突变菌株的抗菌活性及靶点抑制作用。这些菌株分别通过用诺氟沙星和萘啶酸筛选从野生型金黄色葡萄球菌MS5935获得。大多数喹诺酮类药物对两种突变菌株的抗菌活性均低于对野生型菌株的抗菌活性。gyrA突变菌株与grlA突变菌株的最低抑菌浓度比值（MIC比值）在0.125至4之间变化。喹诺酮类药物对拓扑异构酶IV的50%抑制浓度（IC50）与对DNA回旋酶的IC50比值也有所不同，范围为0.177至5.52。观察到MIC比值与IC50比值之间存在显著相关性（r = 0.919；P < 0.001）。这些结果表明，喹诺酮类药物对野生型菌株的抗菌活性不仅涉及拓扑异构酶IV抑制，还涉及DNA回旋酶抑制，并且野生型菌株中的靶点偏好可以通过MIC比值来预测。基于MIC比值，喹诺酮类药物被分为三类。I型喹诺酮类药物（诺氟沙星、依诺沙星、氟罗沙星、环丙沙星、洛美沙星、曲伐沙星、格帕沙星、氧氟沙星和左氧氟沙星）的MIC比值<1，II型喹诺酮类药物（司帕沙星和萘啶酸）的MIC比值>1，III型喹诺酮类药物（加替沙星、帕珠沙星、莫西沙星和克林沙星）的MIC比值为1。I型和II型喹诺酮类药物似乎分别更倾向于作用于拓扑异构酶IV和DNA回旋酶。III型喹诺酮类药物似乎在细菌细胞中对这两种酶的作用水平几乎相同（这种现象称为双靶点特性），并且它们的IC50比值约为2。
