Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions.
Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions.
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DOI：
10.1021/cb400592n
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发表时间：
2013-12-20
影响因子：
4
通讯作者：
Osheroff, Neil
中科院分区：
文献类型：
--
作者：
Aldred, Katie J.;Schwanz, Heidi A.;Li, Gangqin;McPherson, Sylvia A.;Turnbough, Charles L., Jr.;Kerns, Robert J.;Osheroff, Neil
喹诺酮类药物以旋转酶和拓扑异构酶 IV 为靶点，是全世界处方最广泛的抗菌药物。不幸的是，它们的使用受到靶标介导的耐药性日益普遍的威胁。超过 90% 的喹诺酮类耐药突变通过破坏关键的水-金属离子桥协调的酶-药物相互作用来发挥作用。喹唑啉二酮类药物是喹诺酮类药物，但缺乏支持桥相互作用所需的骨架特征。然而，这些化合物具有临床意义，因为它们保留了针对最常见的喹诺酮耐药突变的活性。我们利用化学生物学方法来确定喹唑啉二酮类如何克服炭疽芽孢杆菌拓扑异构酶 IV 中的喹诺酮耐药性。保留抗喹诺酮耐药拓扑异构酶 IV 活性的喹唑啉二酮主要是通过 C7 取代基而不是药物骨架建立新的相互作用。由于一些喹诺酮类药物对人类拓扑异构酶 IIα 具有高度活性，因此我们还确定了临床相关的喹诺酮类药物如何区分细菌酶和人类酶。临床相关的喹诺酮类药物对拓扑异构酶 IIα 的活性较差，因为人类酶不能支持由水-金属离子桥介导的药物相互作用。然而，包含允许喹唑啉二酮克服拓扑异构酶 IV 介导的喹诺酮耐药性的取代基可能会导致与拓扑异构酶 IIα 的交叉反应。因此，设计克服喹诺酮耐药性的药物的一个主要挑战在于识别介导与细菌酶而非人类酶强相互作用的取代基的能力。基于我们对喹诺酮-酶相互作用的理解，我们鉴定了三种化合物，它们对喹诺酮耐药的炭疽芽孢杆菌拓扑异构酶 IV 具有高活性，但对人拓扑异构酶 IIα 具有低活性。
Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by the increasing prevalence of target-mediated drug resistance. Greater than 90% of mutations that confer quinolone resistance act by disrupting enzyme-drug interactions coordinated by a critical water-metal ion bridge. Quinazolinediones are quinolone-like drugs, but lack the skeletal features necessary to support the bridge interaction. These compounds are of clinical interest, however, because they retain activity against the most common quinolone resistance mutations. We utilized a chemical biology approach to determine how quinazolinediones overcome quinolone resistance in Bacillus anthracis topoisomerase IV. Quinazolinediones that retain activity against quinolone-resistant topoisomerase IV do so primarily by establishing novel interactions through the C7 substituent, rather than the drug skeleton. Because some quinolones are highly active against human topoisomerase IIα, we also determined how clinically relevant quinolones discriminate between the bacterial and human enzymes. Clinically relevant quinolones display poor activity against topoisomerase IIα because the human enzyme cannot support drug interactions mediated by the water-metal ion bridge. However, the inclusion of substituents that allow quinazolinediones to overcome topoisomerase IV-mediated quinolone resistance can cause cross-reactivity against topoisomerase IIα. Therefore, a major challenge in designing drugs that overcome quinolone resistance lies in the ability to identify substituents that mediate strong interactions with the bacterial, but not the human, enzymes. Based on our understanding of quinolone-enzyme interactions, we have identified three compounds that display high activity against quinolone-resistant B. anthracis topoisomerase IV but low activity against human topoisomerase IIα.
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影响因子：
5.6
作者：
Hammonds, TR;Foster, SR;Maxwell, A
通讯作者：
Maxwell, A
影响因子：
11.5
作者：
Hooper, DC
通讯作者：
Hooper, DC
DOI：
10.2174/1568011054222364
发表时间：
2005-07-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
Baldwin, E. L.;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：
11.8
作者：
Hooper, DC
通讯作者：
Hooper, DC