Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance
Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance
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DOI：
10.1101/cshperspect.a025320
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发表时间：
2016-09-01
影响因子：
5.4
通讯作者：
Jacoby, George A.
中科院分区：
文献类型：
--
作者：
Hooper, David C.;Jacoby, George A.
喹诺酮类抗菌剂广泛应用于临床医学，是目前唯一一类直接抑制细菌DNA合成的药物。喹诺酮类药物可双重靶向DNA促旋酶和拓扑异构酶IV，与特定结构域和构象结合，从而阻断DNA链通过催化作用，并稳定DNA-酶复合物，该复合物阻断DNA复制装置并在DNA中产生双重断裂，这是其杀菌活性的基础。这些药物的临床使用已经出现耐药性，并且在一些细菌病原体中很常见。耐药机制包括药物靶点亲和力和外排泵表达的突变改变以及耐药基因的获得。两种药物靶酶中的一种或两种中的抗性突变通常分别位于促旋酶和拓扑异构酶IV的GyrA和ParC亚基的局部结构域中，并降低药物与酶-DNA复合物的结合。其他耐药突变发生在控制位于细菌膜中的天然外排泵表达的调控基因中。这些泵具有广泛的底物特征，包括其他抗菌剂以及喹诺酮类。这两种类型的突变可以随着选择压力而积累，并产生高度抗性的菌株。质粒上获得的抗性基因赋予低水平抗性，促进突变高水平抗性的选择。质粒编码的耐药性是由于Qnr蛋白保护靶酶免受喹诺酮类药物作用，这是一种突变的氨基糖苷类修饰酶，也修饰某些喹诺酮类药物，以及移动的外排泵。具有这些机制的质粒通常编码额外的抗菌素耐药性，并可转移包括喹诺酮类在内的多药耐药性。
Quinolone antimicrobials are widely used in clinical medicine and are the only current class of agents that directly inhibit bacterial DNA synthesis. Quinolones dually target DNA gyrase and topoisomerase IV binding to specific domains and conformations so as to block DNA strand passage catalysis and stabilize DNA-enzyme complexes that block the DNA replication apparatus and generate double breaks in DNA that underlie their bactericidal activity. Resistance has emerged with clinical use of these agents and is common in some bacterial pathogens. Mechanisms of resistance include mutational alterations in drug target affinity and efflux pump expression and acquisition of resistance-conferring genes. Resistance mutations in one or both of the two drug target enzymes are commonly in a localized domain of the GyrA and ParC subunits of gyrase and topoisomerase IV, respectively, and reduce drug binding to the enzyme-DNA complex. Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s). These pumps have broad substrate profiles that include other antimicrobials as well as quinolones. Mutations of both types can accumulate with selection pressure and produce highly resistant strains. Resistance genes acquired on plasmids confer low-level resistance that promotes the selection of mutational high-level resistance. Plasmid-encoded resistance is because of Qnr proteins that protect the target enzymes from quinolone action, a mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps. Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones.