Role of the water-metal ion bridge in mediating interactions between quinolones and Escherichia coli topoisomerase IV.
Role of the water-metal ion bridge in mediating interactions between quinolones and Escherichia coli topoisomerase IV.
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DOI：
10.1021/bi500682e
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发表时间：
2014-09-02
期刊：
影响因子：
2.9
通讯作者：
Osheroff N
中科院分区：
文献类型：
--
作者：
Aldred KJ;Breland EJ;Vlčková V;Strub MP;Neuman KC;Kerns RJ;Osheroff N
尽管喹诺酮类药物已在临床使用了几十年，但其药物活性和耐药性的机制仍然难以捉摸。然而，最近的研究表明，临床相关的喹诺酮类药物通过一个关键的水-金属离子桥与炭疽芽孢杆菌（革兰氏阳性）拓扑异构酶IV相互作用，最常见的喹诺酮类药物耐药突变通过破坏这个桥而降低药物活性。作为确定水-金属离子桥是否是喹诺酮-拓扑异构酶相互作用的一般机制的第一步，我们表征了药物与野生型大肠杆菌（格兰氏阴性）拓扑异构酶IV和一系列在预测桥锚定残基中突变的ParC酶（S80L, S80I， S80F和E84K）的相互作用。研究结果强烈表明，水-金属离子桥是喹诺酮类药物抗大肠杆菌拓扑异构酶IV活性的重要机制。尽管水-金属离子桥是喹诺酮类药物广谱作用的共同关键机制，但它在炭疽杆菌和大肠杆菌拓扑异构酶IV中发挥的作用不同。水-金属离子桥是临床相关喹诺酮类药物与革兰氏阳性酶最重要的结合接触。然而，它的主要作用是将临床相关的喹诺酮类药物与大肠杆菌拓扑异构酶IV正确地结合起来。最后，尽管环丙沙星不能增加由几种Ser80和Glu84突变型大肠杆菌酶介导的DNA切割水平，但该药物仍然保留了抑制这些拓扑异构酶IV蛋白整体催化活性的能力。抑制与药物结合平行，表明药物在活性部位的存在足以降低DNA松弛率。
Although quinolones have been in clinical use for decades, the mechanism underlying drug activity and resistance has remained elusive. However, recent studies indicate that clinically relevant quinolones interact with Bacillus anthracis (Gram-positive) topoisomerase IV through a critical water–metal ion bridge and that the most common quinolone resistance mutations decrease drug activity by disrupting this bridge. As a first step toward determining whether the water–metal ion bridge is a general mechanism of quinolone–topoisomerase interaction, we characterized drug interactions with wild-type Escherichia coli (Gram-negative) topoisomerase IV and a series of ParC enzymes with mutations (S80L, S80I, S80F, and E84K) in the predicted bridge-anchoring residues. Results strongly suggest that the water–metal ion bridge is essential for quinolone activity against E. coli topoisomerase IV. Although the bridge represents a common and critical mechanism that underlies broad-spectrum quinolone function, it appears to play different roles in B. anthracis and E. coli topoisomerase IV. The water–metal ion bridge is the most important binding contact of clinically relevant quinolones with the Gram-positive enzyme. However, it primarily acts to properly align clinically relevant quinolones with E. coli topoisomerase IV. Finally, even though ciprofloxacin is unable to increase levels of DNA cleavage mediated by several of the Ser80 and Glu84 mutant E. coli enzymes, the drug still retains the ability to inhibit the overall catalytic activity of these topoisomerase IV proteins. Inhibition parallels drug binding, suggesting that the presence of the drug in the active site is sufficient to diminish DNA relaxation rates.
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影响因子：
4
作者：
Aldred, Katie J.;Schwanz, Heidi A.;Li, Gangqin;McPherson, Sylvia A.;Turnbough, Charles L., Jr.;Kerns, Robert J.;Osheroff, Neil
通讯作者：
Osheroff, Neil
DOI：
10.1016/j.bbrc.2006.07.017
发表时间：
2006-09-15
影响因子：
3.1
作者：
Aubry, Alexandra;Fisher, L. Mark;Cambau, Ernmanuelle
通讯作者：
Cambau, Ernmanuelle
影响因子：
2.9
作者：
Anderson, VE;Zaniewski, RP;Osheroff, N
通讯作者：
Osheroff, N
影响因子：
4.9
作者：
German, Nadezhda;Malik, Muhammad;Kerns, Robert J.
通讯作者：
Kerns, Robert J.
影响因子：
64.8
作者：
Bax, Benjamin D.;Chan, Pan F.;Gwynn, Michael N.
通讯作者：
Gwynn, Michael N.