Mode of action of fluoroquinolones
Mode of action of fluoroquinolones
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DOI：
10.2165/00003495-199958002-00002
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发表时间：
1999-01-01
期刊：
影响因子：
11.5
通讯作者：
Hooper, DC
中科院分区：
文献类型：
--
作者：
Hooper, DC
喹诺酮类药物的作用模式涉及与DNA旋切酶（最初识别的药物靶点）和拓扑异构酶IV（相关的II型拓扑异构酶）的相互作用。在给定的细菌中，这两种酶对许多喹诺酮类药物的相对敏感性通常不同，通常DNA回转酶在革兰氏阴性菌中更敏感，而拓扑异构酶IV在革兰氏阳性菌中更敏感。通常，更敏感的酶代表了基因测试确定的主要药物靶点，但也有鲜为人知的例外记录。喹诺酮、DNA、DNA回转酶或拓扑异构酶IV的三元复合物的形成是通过相互作用发生的，其中喹诺酮结合似乎诱导DNA和拓扑异构酶的变化，这些变化与喹诺酮作用的标志DNA裂解分开发生。螺旋酶a亚基片段的x射线晶体学研究。以及酵母拓扑异构酶IV，它与DNA回转酶和拓扑异构酶IV的亚基都有同源性，已经揭示了可能构成喹诺酮结合位点的结构域，但迄今为止还没有包括DNA和喹诺酮的拓扑异构酶晶体结构的报道。喹诺酮类药物抑制DNA合成需要目标拓扑异构酶具有DNA切割能力，并且复制叉与可逆的喹诺酮-DNA-拓扑异构酶复合物的碰撞将其转化为不可逆的形式。然而，随后从不可逆复合物中产生DNA双链断裂并可能引发细胞死亡的分子因素尚未确定。
The mode of action of quinolones involves interactions with both DNA gyrase, the originally recognised drug target, and topoisomerase IV, a related type II topoisomerase. In a given bacterium these 2 enzymes often differ in their relative sensitivities to many quinolones, and commonly DNA gyrase is more sensitive in Gram-negative bacteria and topoisomerase IV more sensitive in Gram-positive bacteria. Usually the more sensitive enzyme represents the primary drug target determined by genetic tests, but poorly understood exceptions have been documented.The formation of the ternary complex of quinolone, DNA, and either DNA gyrase or topoisomerase IV occurs through interactions in which quinolone binding appears to induce changes in both DNA and the topoisomerase that occur separately from the DNA cleavage that is the hallmark of quinolone action. X-ray crystallographic studies of a fragment of the gyrase A subunit. as well as of yeast topoisomerase IV, which has homology to the subunits of both DNA gyrase and topoisomerase IV, have revealed domains that are likely to constitute quinolone binding sites, but no topoisomerase crystal structures that include DNA and quinolone have been reported to date.Inhibition of DNA synthesis by quinolones requires the targeted topoisomerase to have DNA cleavage capability, and collisions of the replication fork with reversible quinolone-DNA-topoisomerase complexes convert them to an irreversible form. However, the molecular factors that subsequently generate DNA double-strand breaks from the irreversible complexes and that probably initiate cell death have yet to be defined.