Sindelar G, Zhao X, Liew A, Dong Y, Lu T, Zhou J, Domagala J, Drlica K
Public Health Research Institute, New York, New York 10016, USA.
Antimicrob Agents Chemother. 2000 Dec;44(12):3337-43. doi: 10.1128/AAC.44.12.3337-3343.2000.
Mutant prevention concentration (MPC) has been proposed as a new measure of antibiotic potency by which the ability to restrict selection of resistant mutants is evaluated. To determine whether MPC provides potency information unavailable from the more customary measurement of the MIC, 18 fluoroquinolones were examined for their ability to block the growth of Mycobacterium smegmatis and to select resistant mutants from wild-type populations. Both MPC and MIC were affected by changes in the moiety at the fluoroquinolone C-8 position and in alkyl groups attached to the C-7 piperazinyl ring. When eight resistant mutants, altered in the gyrase A protein, were tested with fluoroquinolones having either a methoxy or a hydrogen at the C-8 position, the MIC for the most resistant mutant correlated better with the MPC than did the MIC for wild-type cells. For C-8-fluorine derivatives, which were generally less active than the C-8-methoxy compounds but which were more active than C-8-hydrogen derivatives, the MICs for both the mutant and the wild type correlated well with the MPCs. Thus, measurement of the MICs for wild-type cells can reflect the ability of a quinolone to restrict the selection of resistance, but often it does not. With the present series of compounds, the most potent contained a C-8-methoxy and a small group attached to the C-7 ring.
突变预防浓度(MPC)已被提议作为评估抗生素效力的一项新指标,通过该指标可评估限制耐药突变体选择的能力。为确定MPC是否能提供从更常用的最低抑菌浓度(MIC)测量中无法获得的效力信息,对18种氟喹诺酮类药物抑制耻垢分枝杆菌生长以及从野生型群体中选择耐药突变体的能力进行了研究。MPC和MIC均受氟喹诺酮C-8位部分以及连接在C-7哌嗪环上的烷基变化的影响。当用C-8位为甲氧基或氢的氟喹诺酮类药物对8种在gyrase A蛋白上发生改变的耐药突变体进行测试时,最耐药突变体的MIC与MPC的相关性比野生型细胞的MIC更好。对于C-8氟衍生物,其活性通常低于C-8甲氧基化合物,但高于C-8氢衍生物,突变体和野生型的MIC与MPC均具有良好的相关性。因此,测量野生型细胞的MIC可以反映喹诺酮类药物限制耐药性选择的能力,但通常并非如此。在本系列化合物中,效力最强的含有C-8甲氧基和连接在C-7环上的一个小基团。