Quinolones: action and resistance updated.
Quinolones: action and resistance updated.
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DOI：
10.2174/156802609789630947
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发表时间：
2009
影响因子：
3.4
通讯作者：
Zhao X
中科院分区：
文献类型：
--
作者：
Drlica K;Hiasa H;Kerns R;Malik M;Mustaev A;Zhao X
喹诺酮类将DNA促旋酶和DNA拓扑异构酶IV捕获在DNA上作为复合物，其中DNA被破坏但被蛋白质限制。早期的研究表明，药物结合主要发生在GyrA（促旋酶）和ParC（拓扑异构酶IV）蛋白的沿着螺旋-4。然而，最近的X射线晶体学显示药物插入切割DNA的-1和+1核苷酸之间，药物的一端延伸到螺旋-4。这两种模式可能反映了复杂地层中不同的构造步骤。药物-酶-DNA复合物形成的结果是DNA复制的可逆抑制;细胞死亡是由随后的事件引起的，其中细菌染色体通过两种知之甚少的途径片段化。在一个途径中，染色体断裂刺激导致细胞死亡的高毒性活性氧物质的过度积累。喹诺酮类药物耐药性逐步出现时，通过选择性扩增的突变体的药物浓度高于MIC和MPC以下，所观察到的静态琼脂平板试验，动态体外系统，和实验感染的兔子。MIC和MPC之间的差距可以通过化合物设计来缩小，该化合物设计应该限制抗性的出现。抗药性可能变得越来越重要，因为已报告了三种类型的质粒携带的抗药性。
The quinolones trap DNA gyrase and DNA topoisomerase IV on DNA as complexes in which the DNA is broken but constrained by protein. Early studies suggested that drug binding occurs largely along helix-4 of the GyrA (gyrase) and ParC (topoisomerase IV) proteins. However, recent X-ray crystallography shows drug intercalating between the -1 and +1 nucleotides of cut DNA, with only one end of the drug extending to helix-4. These two models may reflect distinct structural steps in complex formation. A consequence of drug-enzyme-DNA complex formation is reversible inhibition of DNA replication; cell death arises from subsequent events in which bacterial chromosomes are fragmented through two poorly understood pathways. In one pathway, chromosome fragmentation stimulates excessive accumulation of highly toxic reactive oxygen species that are responsible for cell death. Quinolone resistance arises stepwise through selective amplification of mutants when drug concentrations are above the MIC and below the MPC, as observed with static agar plate assays, dynamic in vitro systems, and experimental infection of rabbits. The gap between MIC and MPC can be narrowed by compound design that should restrict the emergence of resistance. Resistance is likely to become increasingly important, since three types of plasmid-borne resistance have been reported.
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影响因子：
3.7
作者：
Boyd LB;Atmar RL;Randall GL;Hamill RJ;Steffen D;Zechiedrich L
通讯作者：
Zechiedrich L
影响因子：
4.9
作者：
Campion, JJ;McNamara, PJ;Evans, ME
通讯作者：
Evans, ME
影响因子：
4.9
作者：
Boyd, Lauren Becnel;Maynard, Merry J.;Zechiedrich, Lynn
通讯作者：
Zechiedrich, Lynn
DOI：
10.1073/pnas.0401595101
发表时间：
2004-05-11
影响因子：
11.1
作者：
Corbett, KD;Shultzaberger, RK;Berger, JM
通讯作者：
Berger, JM
影响因子：
3.9
作者：
BEJAR, S;BOUCHE, JP
通讯作者：
BOUCHE, JP