Mechanisms of action of antimicrobials: Focus on fluoroquinolones
Mechanisms of action of antimicrobials: Focus on fluoroquinolones
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DOI：
10.1086/319370
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发表时间：
2001-03-15
影响因子：
11.8
通讯作者：
Hooper, DC
中科院分区：
文献类型：
--
作者：
Hooper, DC
在抗菌药物的开发中已经利用了五种细菌靶标：细胞壁合成、蛋白质合成、核糖核酸合成、脱氧核糖核酸（DNA）合成和中间代谢。由于对与这些靶点相互作用的药物的耐药性很普遍，因此新的抗菌剂及其作用机制的理解至关重要。氟喹诺酮类药物是DNA合成的唯一直接抑制剂;通过与酶-DNA复合物结合，它们稳定由DNA促旋酶和拓扑异构酶IV产生的DNA链断裂。药物、酶和DNA的三元复合物阻止复制叉的进展。氟喹诺酮类的细胞毒性可能是一个2步过程，涉及（1）拓扑异构酶-喹诺酮-DNA复合物转化为不可逆形式和（2）通过拓扑异构酶变性产生双链断裂。从步骤1到步骤2的过渡所需的分子因素仍不清楚，但细胞死亡的下游途径可能与其他杀菌抗菌剂所使用的途径重叠。氟喹诺酮耐药突变体和纯化的拓扑异构酶的研究表明，许多喹诺酮类药物对这两个目标有不同的活动。对两个靶点具有相似活性的药物可能不太可能选择从头耐药。
Five bacterial targets have been exploited in the development of antimicrobial drugs: cell wall synthesis, protein synthesis, ribonucleic acid synthesis, deoxyribonucleic acid (DNA) synthesis, and intermediary metabolism. Because resistance to drugs that interact with these targets is widespread, new antimicrobials and an understanding of their mechanisms of action are vital. The fluoroquinolones are the only direct inhibitors of DNA synthesis; by binding to the enzyme-DNA complex, they stabilize DNA strand breaks created by DNA gyrase and topoisomerase IV. Ternary complexes of drug, enzyme, and DNA block progress of the replication fork. Cytotoxicity of fluoroquinolones is likely a 2-step process involving (1) conversion of the topoisomerase-quinolone-DNA complex to an irreversible form and (2) generation of a double-strand break by denaturation of the topoisomerase. The molecular factors necessary for the transition from step 1 to step 2 remain unclear, but downstream pathways for cell death may overlap with those used by other bactericidal antimicrobials. Studies of fluoroquinolone-resistant mutants and purified topoisomerases indicate that many quinolones have differing activities against the two targets. Drugs with similar activities against both targets may prove less likely to select de novo resistance.