Mode of action of the new quinolones: New data
Mode of action of the new quinolones: New data
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新喹诺酮类药物的作用方式：新数据
DOI：
10.1007/bf01966994
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发表时间：
1991
影响因子：
4.5
通讯作者：
J. Wolfson
中科院分区：
文献类型：
--
作者：
D. C. Hooper;J. Wolfson
喹诺酮类药物与其靶标 DNA 旋转酶和 DNA 分子相互作用的新细节来自大肠杆菌和其他细菌野生型菌株的抗性突变体的 gyrA 基因的核苷酸序列以及旋转酶 A 胰蛋白酶片段的研究，所有这些都表明氨基末端结构域在喹诺酮作用中的重要性。 DNA 超扭曲的改变也与喹诺酮敏感性改变有关，可能是通过对 DNA 旋转酶表达的间接影响。在 ATP 存在下，相关浓度的诺氟沙星与 DNA 旋转酶和 DNA 的复合物的特异性结合、DNA 结合的协同性以及萘啶酸的晶体结构已经产生了一种模型，其中喹诺酮类药物与 DNA 旋转酶产生的单链 DNA 口袋协同结合。喹诺酮类药物针对 DNA 旋转酶及其真核同系物拓扑异构酶 II 的相对活性各不相同，并且在一些测定中，针对真核酶的作用增强与基因毒性相关。喹诺酮类药物对细菌 DNA 合成的抑制可能与某些物种的 MIC 相关，但不同物种间透化细胞中药物蓄积和 DNA 合成抑制的比较很难解释。除了与 DNA 旋转酶的相互作用之外，喹诺酮类药物杀死细菌所需的具体因素仍然难以捉摸，但包括氧气和新蛋白质的合成。 SOS 蛋白的协调表达似乎对于喹诺酮类致死性不是必需的。喹诺酮类和β-内酰胺选择性减少杀伤作用的两个独立突变体表明，具有不同靶标的此类药剂的杀菌活性途径存在重叠。
New details of the molecular interactions of quinolones with their target DNA gyrase and DNA have come from the nucleotide sequences of thegyrAgenes from resistant mutants ofEscherichia coliand wild-type strains of other bacteria and studies of gyrase A tryptic fragments, all suggesting the importance of an amino-terminal domain in quinolone action. Alterations in DNA supertwisting were also associated with altered quinolone susceptibility, possibly by indirect effects on DNA gyrase expression. Specific binding of relevant concentrations of norfloxacin to a complex of DNA gyrase and DNA in the presence of ATP, the cooperativity of DNA binding, and the crystalline structure of nalidixic acid have led to a model in which quinolones bind cooperatively to a pocket of single-strand DNA created by DNA gyrase. Quinolones vary in their relative activity against DNA gyrase and its eukaryotic homolog topoisomerase II, and in some assays increased action against the eukaryotic enzyme was associated with genotoxicity. Inhibition of bacterial DNA synthesis by quinolones may correlate with MICs in some species, but comparisons of drug accumulation and inhibition of DNA synthesis in permeabilized cells among species have been difficult to interpret. The specific factors necessary for bacterial killing by quinolones in addition to interaction with DNA gyrase have remained elusive, but include oxygen and new protein synthesis. The coordinate expression of the SOS proteins appears not to be necessary for quinolone lethality. Two independent mutants with selective reduced killing by quinolones and beta-lactams indicate overlap in the pathways of bactericidal activity of these classes of agents with distinct targets.
影响因子：
2.9
作者：
Linus L. Shen;J. Baranowski;A. Pernet
通讯作者：
Linus L. Shen;J. Baranowski;A. Pernet