Examining the Impact of Antimicrobial Fluoroquinolones on Human DNA Topoisomerase IIα and IIβ
Examining the Impact of Antimicrobial Fluoroquinolones on Human DNA Topoisomerase IIα and IIβ
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DOI：
10.1021/acsomega.8b03428
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发表时间：
2019-02-01
期刊：
影响因子：
4.1
通讯作者：
Deweese, Joseph E.
中科院分区：
文献类型：
--
作者：
Fief, Cole A.;Hoang, Kristine G.;Deweese, Joseph E.
氟喹诺酮类是一类广泛使用的抗生素，对革兰氏阳性菌、革兰氏阴性菌和一些非典型微生物具有广泛的活性。不幸的是，这些药物与显著的不良事件相关，包括神经病变、肌腱病变、心律异常和精神健康副作用。氟喹诺酮类药物引起这些毒性的机制尚不清楚。抗菌作用机制涉及破坏细菌中II型拓扑异构酶（即拓扑异构酶IV和DNA促旋酶）的催化机制。氟喹诺酮类抑制酶连接切割DNA的能力，并导致单链和双链DNA断裂。因此，研究人类拓扑异构酶II是否参与介导与喹诺酮类药物相关的不良事件具有重要意义。先前的研究表明，人类拓扑异构酶II α和II β对高水平的环丙沙星有一定的反应。然而，尚不清楚这些研究中使用的环丙沙星浓度是否与患者常规可达到的浓度相对应。因此，本研究开始检查三种临床相关的氟喹诺酮类药物沿着两种较老的药物，以确定这些化合物在更接近典型患者血浆值的药物浓度下是否显示出对拓扑异构酶II α和II β的活性。根据我们的证据，所研究的喹诺酮类药物都不能毒害任何一种人类酶的DNA切割。环丙沙星、去乙烯-环丙沙星和最近从市场上撤下的吉非替尼在200-300 μ M的浓度下能够抑制拓扑异构酶II介导的DNA松弛。在这些数据的基础上，我们认为人类拓扑异构酶II不太可能是这些不良事件的主要原因，需要确定其他靶点以阐明喹诺酮类药物毒性的机制。
Fluoroquinolones are a class of widely prescribed antibiotics with a broad range of activity against Gram-positive, Gram-negative, and some atypical microbes. Unfortunately, these drugs are associated with significant adverse events including neuropathy, tendinopathy, cardiac rhythm abnormalities, and mental health side effects. The mechanism by which fluoroquinolones cause many of these toxicities is unknown. The antibacterial mechanism of action involves disruption of the catalytic mechanism of type-II topoisomerases in bacteria, namely topoisomerase IV and DNA gyrase. Fluoroquinolones inhibit the ability of the enzymes to ligate cleaved DNA and result in single- and double-stranded DNA breaks. Thus, there is an interest in investigating whether human topoisomerase II is involved in mediating the adverse events associated with quinolones. Previous studies demonstrate some response of human topoisomerase II alpha and II beta to high levels of ciprofloxacin. However, it is not clear whether the concentration of ciprofloxacin utilized in those studies corresponds to concentrations that would be routinely achievable in patients. Therefore, this study set out to examine three clinically relevant fluoroquinolones along with two older agents to determine whether these compounds display activity against topoisomerase II alpha and II beta at drug concentrations that more closely approximate typical patient plasma values. On the basis of our evidence, none of the quinolones studied were able to poison DNA cleavage by either human enzyme. Ciprofloxacin, desethylene-ciprofloxacin, and the recently removed from market gemifloxacin were able to inhibit topoisomerase II-mediated DNA relaxation at concentrations of 200-300 mu M. On the basis of these data, we propose that human topoisomerase II is not likely to be the main cause of these adverse events and that additional targets need to be identified to clarify the mechanisms underlying quinolone toxicities.