Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria
Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria
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DOI：
10.1128/aac.44.12.3337-3343.2000
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发表时间：
2000-12-01
影响因子：
4.9
通讯作者：
Drlica, K
中科院分区：
文献类型：
--
作者：
Sindelar, G;Zhao, XL;Drlica, K
突变预防浓度（MPC）已被提出作为一种新的抗生素效力的措施，通过它来评估限制选择耐药突变体的能力。为了确定MPC是否提供了从更常规的测量中无法获得的效力信息，检查了18种氟喹诺酮类药物阻断耻垢分枝杆菌生长和从野生型群体中选择抗性突变体的能力。MPC和MIC均受到氟喹诺酮C-8位部分和连接至C-7哌嗪基环的烷基的变化的影响。当八个耐药突变体，改变了促旋酶A蛋白，与氟喹诺酮类药物在C-8位的甲氧基或氢进行了测试，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，但活性高于C-8-氢衍生物，突变体和野生型的MIC与MPC相关性良好。因此，测量野生型细胞的MIC可以反映喹诺酮限制抗性选择的能力，但通常不能。对于本系列化合物，最有效的化合物含有C-I-甲氧基和连接到C-7环的小基团。
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 MIG, 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,vith 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-l-methoxy and a small group attached to the C-7 ring.