Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914
Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914
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DOI：
10.1074/jbc.m115.663534
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发表时间：
2015-08-21
影响因子：
4.8
通讯作者：
Walkup, Grant K.
中科院分区：
文献类型：
--
作者：
Kern, Gunther;Palmer, Tiffany;Walkup, Grant K.
我们表征了 AZD0914（AZD0914 以下将称为 ETX0914（Entasis Therapeutics））对淋病奈瑟菌 II 型拓扑异构酶促旋酶和拓扑异构酶 IV 的抑制作用，AZD0914 是一种新型螺嘧啶三酮抗菌化合物，目前正处于治疗耐药性淋病的临床试验中。 AZD0914 对淋病奈瑟菌具有有效的杀菌活性，包括多重耐药菌株和关键的革兰氏阳性菌、挑剔的革兰氏阴性菌、非典型菌和厌氧菌（Huband, M. D.、Bradford, P. A.、Otterson, L. G.、Basrab, G. S.、Giacobe, R. A.、Paty, S. A.、Kutschke, A. C.、Johnstone, M. R.、Potter, M. E.、Miller, P. F. 和 Mueller, J. P. (2014) AZD0914 的体外抗菌活性：一种新型螺嘧啶三酮 DNA 旋转酶/拓扑异构酶抑制剂，对革兰氏阳性菌、挑剔的革兰氏阴性菌和非典型细菌具有有效的抗菌活性 59， 467-474）。 AZD0914 优先抑制大肠杆菌中的 DNA 生物合成，并诱导大肠杆菌中对 DNA 损伤的 SOS 反应。 AZD0914 稳定了淋病奈瑟菌旋转酶和拓扑异构酶 IV 的酶-DNA 切割复合物。在氟喹诺酮抗性突变酶中，AZD0914 抑制淋病奈瑟菌旋转酶超螺旋和稳定裂解复合物的效力增强。当氟喹诺酮抗性突变体中存在赋予 AZD0914 轻度抗性的突变时，环丙沙星抑制超螺旋和稳定裂解复合物的效力增加超过 20 倍。与环丙沙星相反，在 AZD0914 存在下，从 DNA-旋转酶-抑制剂复合物中除去镁后，切割的 DNA 不会发生重新连接。 AZD0914 对人 II 型拓扑异构酶 α 和 β 的抑制效力相对较低。
We characterized the inhibition of Neisseria gonorrhoeae type II topoisomerases gyrase and topoisomerase IV by AZD0914 (AZD0914 will be henceforth known as ETX0914 (Entasis Therapeutics)), a novel spiropyrimidinetrione antibacterial compound that is currently in clinical trials for treatment of drug-resistant gonorrhea. AZD0914 has potent bactericidal activity against N. gonorrhoeae, including multidrug-resistant strains and key Gram-positive, fastidious Gram-negative, atypical, and anaerobic bacterial species (Huband, M. D., Bradford, P. A., Otterson, L. G., Basrab, G. S., Giacobe, R. A., Patey, S. A., Kutschke, A. C., Johnstone, M. R., Potter, M. E., Miller, P. F., and Mueller, J. P. (2014) In Vitro Antibacterial Activity of AZD0914: A New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-positive, Fastidious Gram-negative, and Atypical Bacteria. Antimicrob. Agents Chemother. 59, 467-474). AZD0914 inhibited DNA biosynthesis preferentially to other macromolecules in Escherichia coli and induced the SOS response to DNA damage in E. coli. AZD0914 stabilized the enzyme-DNA cleaved complex for N. gonorrhoeae gyrase and topoisomerase IV. The potency of AZD0914 for inhibition of supercoiling and the stabilization of cleaved complex by N. gonorrhoeae gyrase increased in a fluoroquinolone-resistant mutant enzyme. When a mutation, conferring mild resistance to AZD0914, was present in the fluoroquinolone-resistant mutant, the potency of ciprofloxacin for inhibition of supercoiling and stabilization of cleaved complex was increased greater than 20-fold. In contrast to ciprofloxacin, religation of the cleaved DNA did not occur in the presence of AZD0914 upon removal of magnesium from the DNA-gyrase-inhibitor complex. AZD0914 had relatively low potency for inhibition of human type II topoisomerases alpha and beta.