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Unraveling the antitrypanosomal mechanism of benznidazole and related 2-nitroimidazoles: From prodrug activation to DNA damage
Molecular Microbiology ( IF 3.6 ) Pub Date : 2021-06-01 , DOI: 10.1111/mmi.14763
Ambika Dattani 1 , Isatou Drammeh 1 , Aishah Mahmood 1 , Mahbubur Rahman 1 , Joanna Szular 1 , Shane R Wilkinson 1
Affiliation  

Nitroheterocycles represent an important class of compound used to treat trypanosomiasis. They often function as prodrugs and can undergo type I nitroreductase (NTR1)-mediated activation before promoting their antiparasitic activities although the nature of these downstream effects has yet to be determined. Here, we show that in an NTR1-dependent process, benznidazole promotes DNA damage in the nuclear genome of Trypanosoma brucei, providing the first direct link between activation of this prodrug and a downstream trypanocidal mechanism. Phenotypic and protein expression studies revealed that components of the trypanosome’s homologous recombination (HR) repair pathway (TbMRE11, γH2A, TbRAD51) cooperate to resolve the benznidazole-induced damage, indicating that the prodrug-induced lesions are most likely double stand DNA breaks, while the sequence/recruitment kinetics of these factors parallels that in other eukaryotes HR systems. When extended to other NTR1-activated 2-nitroimidazoles, some were shown to promote DNA damage. Intriguingly, the lesions induced by these required TbMRE11 and TbCSB activities to fix leading us to postulate that TbCSB may operate in systems other than the transcription-coupled nucleotide excision repair pathway. Understanding how existing trypanosomal drugs work will aid future drug design and help unlock novel reactions/pathways that could be exploited as targets for therapeutic intervention.

中文翻译:

解开苯并硝唑和相关 2-硝基咪唑的抗锥虫机制:从前药激活到 DNA 损伤

硝基杂环代表一类重要的用于治疗锥虫病的化合物。它们通常作为前药发挥作用,在促进其抗寄生虫活性之前可以进行 I 型硝基还原酶 (NTR1) 介导的活化,尽管这些下游效应的性质尚未确定。在这里,我们表明在 NTR1 依赖性过程中,苯并硝唑促进布氏锥虫核基因组中的 DNA 损伤,提供了该前药激活与下游锥虫杀灭机制之间的第一个直接联系。表型和蛋白质表达研究表明,锥虫同源重组 (HR) 修复途径的组分 (TbMRE11、γH2A、TbRAD51) 协同解决苯并硝唑诱导的损伤,表明前药诱导的损伤很可能是双链 DNA 断裂,而这些因素的序列/招募动力学与其他真核生物 HR 系统中的相似。当扩展到其他 NTR1 激活的 2-硝基咪唑时,一些被证明会促进 DNA 损伤。有趣的是,由这些需要 TbMRE11 和 TbCSB 活动引起的损伤导致我们假设 TbCSB 可能在转录偶联核苷酸切除修复途径以外的系统中运作。
更新日期:2021-06-01
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