Interactions between Quinolones and Bacillus anthracis Gyrase and the Basis of Drug Resistance.
Interactions between Quinolones and Bacillus anthracis Gyrase and the Basis of Drug Resistance.
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DOI：
10.1021/acs.biochem.7b00203
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发表时间：
2017-08-15
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：
Ashley RE;Lindsey RH Jr;McPherson SA;Turnbough CL Jr;Kerns RJ;Osheroff N
旋转酶似乎是喹诺酮类抗菌药在多种病原菌中的主要细胞靶点，包括炭疽芽孢杆菌，炭疽病的病原体。鉴于这种II型拓扑异构酶作为药物靶点的重要性，了解喹诺酮类药物如何与旋转酶相互作用以及特定的突变如何导致耐药性是至关重要的。然而，对于规范的旋转酶来说，这些重要的问题尚未解决。因此，我们利用一种机制方法来表征喹诺酮类药物与野生型炭疽杆菌旋转酶和含有最常见的喹诺酮类耐药突变的酶的相互作用。结果表明，临床上相关的喹诺酮类药物通过水-金属离子桥与酶相互作用，其中非催化的二价金属离子被药物的C3/C4酮酸螯合。与已检测的其他细菌II型拓扑异构酶不同，该桥主要通过单一残基(Ser85)锚定于旋转酶。取代喹诺酮C7和C8位上的基团产生的药物对水-金属离子桥的依赖性较低，并克服了耐药性。因此，通过分析药物与来自单个细菌的II型拓扑异构酶的相互作用，有可能确定特定的喹诺酮类衍生物，这些衍生物可以克服重要病原菌的靶向介导的耐药性。
Gyrase appears to be the primary cellular target for quinolone antibacterials in multiple pathogenic bacteria, including Bacillus anthracis, the causative agent of anthrax. Given the significance of this type II topoisomerase as a drug target, it is critical to understand how quinolones interact with gyrase and how specific mutations lead to resistance. However, these important issues have yet to be addressed for a canonical gyrase. Therefore, we utilized a mechanistic approach to characterize interactions of quinolones with wild-type B. anthracis gyrase and enzymes containing the most common quinolone resistance mutations. Results indicate that clinically relevant quinolones interact with the enzyme through a water–metal ion bridge in which a noncatalytic divalent metal ion is chelated by the C3/C4 keto acid of the drug. In contrast to other bacterial type II topoisomerases that have been examined, the bridge is anchored to gyrase primarily through a single residue (Ser85). Substitution of groups at the quinolone C7 and C8 positions generated drugs that were less dependent on the water–metal ion bridge and overcame resistance. Thus, by analyzing the interactions of drugs with type II topoisomerases from individual bacteria, it may be possible to identify specific quinolone derivatives that can overcome target-mediated resistance in important pathogenic species.
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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
影响因子：
10.5
作者：
Crisona, NJ;Strick, TR;Cozzarelli, NR
通讯作者：
Cozzarelli, NR
DOI：
10.1039/c003759a
发表时间：
2010-07
期刊：
Metallomics : integrated biometal science
影响因子：
--
作者：
Deweese JE;Osheroff N
通讯作者：
Osheroff N
影响因子：
2.9
作者：
Aldred KJ;Breland EJ;Vlčková V;Strub MP;Neuman KC;Kerns RJ;Osheroff N
通讯作者：
Osheroff N
影响因子：
64.8
作者：
Bax, Benjamin D.;Chan, Pan F.;Gwynn, Michael N.
通讯作者：
Gwynn, Michael N.