Specific inhibition of the eubacterial DNA ligase by arylamino compounds
Specific inhibition of the eubacterial DNA ligase by arylamino compounds
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DOI：
10.1128/aac.43.11.2766
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发表时间：
1999-11-01
影响因子：
4.9
通讯作者：
Tilley, L
中科院分区：
文献类型：
--
作者：
Ciarrocchi, G;MacPhee, DG;Tilley, L
所有已知的DNA连接酶通过非常相似的机制催化双链DNA中相邻末端之间的磷酸二酯键的形成。然而，连接酶家族可以分为两类：需要NAD（+）作为辅因子的真细菌连接酶，以及来自病毒、古细菌和真核生物的使用ATP的其他连接酶。区分不同来源的DNA连接酶的药物可能具有抗菌活性。我们现在报道一组芳氨基化合物，包括一些常用的抗疟和抗炎药物和一系列新的双喹啉化合物，是真细菌DNA连接酶的特异性抑制剂。这组抑制剂的成员具有不同的杂环系统，具有共同的氨基侧链，其中两个氮被四个碳原子分开。效力（而非作用特异性）受抑制剂的DNA结合特征的影响，且抑制作用与NAD（+）无竞争性。芳氨基化合物似乎在体内靶向真细菌DNA连接酶，因为已经用ATP依赖性T4 DNA连接酶拯救的沙门氏菌Lig（-）菌株比亲本沙门氏菌菌株更不敏感。
All known DNA ligases catalyze the formation of a phosphodiester linkage between adjacent termini in double-stranded DNA via very similar mechanisms. The ligase family can, however, be divided into two classes: eubacterial ligases, which require NAD(+) as a cofactor, and other ligases, from viruses, archaea, and eukaryotes, which use ATP. Drugs that discriminate between DNA ligases from different sources may have antieubacterial activity. We now report that a group of arylamino compounds, including some commonly used antimalarial and anti-inflammatory drugs and a novel series of bisquinoline compounds, are specific inhibitors of eubacterial DNA ligases. Members of this group of inhibitors have different heterocyclic ring systems with a common amino side chain in which the two nitrogens are separated by four carbon atoms. The potency, but not the specificity of action, is influenced by the DNA-binding characteristics of the inhibitor, and the inhibition is noncompetitive with respect to NAD(+). The arylamino compounds appear to target eubacterial DNA ligase in vivo, since a Salmonella Lig(-) strain that has been rescued with the ATP-dependent T4 DNA ligase is less sensitive than the parental Salmonella strain.