Fukuda H, Hori S, Hiramatsu K
Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi, Shimotsuga, Tochigi 329-0114, Japan.
Antimicrob Agents Chemother. 1998 Aug;42(8):1917-22. doi: 10.1128/AAC.42.8.1917.
Alternate mutations in the grlA and gyrA genes were observed through the first- to fourth-step mutants which were obtained from four Staphylococcus aureus strains by sequential selection with several fluoroquinolones. The increases in the MICs of gatifloxacin accompanying those mutational steps suggest that primary targets of gatifloxacin in the wild type and the first-, second-, and third-step mutants are wild-type topoisomerase IV (topo IV), wild-type DNA gyrase, singly mutated topo IV, and singly mutated DNA gyrase, respectively. Gatifloxacin had activity equal to that of tosufloxacin and activity more potent than those of norfloxacin, ofloxacin, ciprofloxacin, and sparfloxacin against the second-step mutants (grlA gyrA; gatifloxacin MIC range, 1.56 to 3.13 microg/ml) and had the most potent activity against the third-step mutants (grlA gyrA grlA; gatifloxacin MIC range, 1.56 to 6.25 microg/ml), suggesting that gatifloxacin possesses the most potent inhibitory activity against singly mutated topo IV and singly mutated DNA gyrase among the quinolones tested. Moreover, gatifloxacin selected resistant mutants from wild-type and the second-step mutants at a low frequency. Gatifloxacin possessed potent activity (MIC, 0.39 microg/ml) against the NorA-overproducing strain S. aureus NY12, the norA transformant, which was slightly lower than that against the parent strain SA113. The increases in the MICs of the quinolones tested against NY12 were negatively correlated with the hydrophobicity of the quinolones (correlation coefficient, -0.93; P < 0.01). Therefore, this slight decrease in the activity of gatifloxacin is attributable to its high hydrophobicity. Those properties of gatifloxacin likely explain its good activity against quinolone-resistant clinical isolates of S. aureus harboring the grlA, gyrA, and/or norA mutations.
通过对从4株金黄色葡萄球菌菌株经多种氟喹诺酮类药物连续筛选获得的第一代至第四代突变体进行观察，发现grlA和gyrA基因存在交替突变。随着这些突变步骤，加替沙星的最低抑菌浓度（MIC）增加，这表明野生型以及第一代、第二代和第三代突变体中，加替沙星的主要作用靶点分别是野生型拓扑异构酶IV（topo IV）、野生型DNA回旋酶、单突变的topo IV和单突变的DNA回旋酶。加替沙星对第二代突变体（grlA gyrA；加替沙星MIC范围为1.56至3.13μg/ml）的活性与托氟沙星相当，且比对诺氟沙星、氧氟沙星、环丙沙星和司帕沙星的活性更强，对第三代突变体（grlA gyrA grlA；加替沙星MIC范围为1.56至6.25μg/ml）的活性最强，这表明在所测试的喹诺酮类药物中，加替沙星对单突变的topo IV和单突变的DNA回旋酶具有最强的抑制活性。此外，加替沙星从野生型和第二代突变体中筛选耐药突变体的频率较低。加替沙星对NorA过表达菌株金黄色葡萄球菌NY12（norA转化体）具有较强活性（MIC为0.39μg/ml），略低于对亲本菌株SA113的活性。所测试的喹诺酮类药物对NY12的MIC增加与喹诺酮类药物的疏水性呈负相关（相关系数为-0.93；P<0.01）。因此，加替沙星活性的这种轻微下降归因于其高疏水性。加替沙星的这些特性可能解释了其对携带grlA、gyrA和/或norA突变的耐喹诺酮类金黄色葡萄球菌临床分离株具有良好活性的原因。
