Use of Gyrase Resistance Mutants To Guide Selection of 8-Methoxy-Quinazoline-2,4-Diones
Use of Gyrase Resistance Mutants To Guide Selection of 8-Methoxy-Quinazoline-2,4-Diones
复制标题
DOI：
10.1128/aac.00330-08
复制
发表时间：
2008-11-01
影响因子：
4.9
通讯作者：
Kerns, Robert J.
中科院分区：
文献类型：
--
作者：
German, Nadezhda;Malik, Muhammad;Kerns, Robert J.
利用大肠杆菌等基因菌株合成了一系列1-环丙基-8-甲氧基-喹唑啉-2,4-二酮，并对其降低gyrase耐药突变体与野生型gyr（+）的MIC比值进行了评价。降低该比值的二酮特征是3-氨基和C-7环结构（3-氨基甲基吡咯烷基< 3-氨基吡咯烷基<重氮双环< 2-乙基哌嗪基）。野生型MIC也降低。通过测试最活跃的衍生物，许多gyrA抗性突变型与野生型细胞一样敏感，甚至更敏感。活性最高的2,4-二酮衍生物对两种抗喹诺酮类gyrB突变体的活性也高于对野生型细胞的活性。就致死率而言，最具抑菌性的2,4-二酮杀灭大肠杆菌的速度几乎不受gyrA耐药性突变的影响，其杀灭速度与其同源物氟喹诺酮相似，为最低致死率的10倍。用野生型大肠杆菌在琼脂上进行群体分析，结果表明，最具活性的2,4-二酮的突变体选择窗口比同源物氟喹诺酮或环丙沙星的突变体选择窗口窄。这些数据说明了一种指导早期抗菌药物选择的新方法。利用抗突变活性（即突变菌株的抗菌MIC与野生型菌株的抗菌MIC之比）作为结构-功能选择标准，可以与旨在降低对野生型生物的抗菌MIC的传统努力相结合，以更有效地提供对野生型和突变型细胞都有活性的铅分子。
A series of 1-cyclopropyl-8-methoxy-quinazoline-2,4-diones was synthesized and evaluated for lowering the ratio of the antimicrobial MIC in gyrase resistance mutants to that in the gyr(+) (wild type) using isogenic strains of Escherichia coli. Dione features that lowered this ratio were a 3-amino group and C-7 ring structure (3-aminomethyl pyrrolidinyl < 3-aminopyrrolidinyl < diazobicyclo < 2-ethyl piperazinyl). The wild-type MIC was also lowered. With the most active derivative tested, many gyrA resistance mutant types were as susceptible as, or more susceptible than, wild-type cells. The most active 2,4-dione derivatives were also more active with two quinolone-resistant gyrB mutants than with wild- type cells. With respect to lethality, the most bacteriostatic 2,4-dione killed E. coli at a rate that was affected little by a gyrA resistance mutation, and it exhibited a rate of killing similar to its cognate fluoroquinolone at 10 x the MIC. Population analysis with wild- type E. coli applied to agar showed that the mutant selection window for the most active 2,4-dione was narrower than that for the cognate fluoroquinolone or for ciprofloxacin. These data illustrate a new approach to guide early-stage antimicrobial selection. Use of antimutant activity (i.e., ratio of the antimicrobial MIC in a mutant strain to the antimicrobial MIC in a wild-type strain) as a structure-function selection criterion can be combined with traditional efforts aimed at lowering antimicrobial MICs against wild-type organisms to more effectively afford lead molecules with activity against both wild- type and mutant cells.