The Antibiotic Monensin Causes Cell Cycle Disruption of Toxoplasma gondii Mediated through the DNA Repair Enzyme TgMSH-1
The Antibiotic Monensin Causes Cell Cycle Disruption of Toxoplasma gondii Mediated through the DNA Repair Enzyme TgMSH-1
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DOI：
10.1128/aac.01092-10
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发表时间：
2011-02-01
影响因子：
4.9
通讯作者：
Arrizabalaga, Gustavo
中科院分区：
文献类型：
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作者：
Lavine, Mark D.;Arrizabalaga, Gustavo
莫能菌素是一种聚醚类离子载体抗生素，广泛用于动物球虫病的防治。尽管其在兽医学中的重要性，但对其作用方式和球虫寄生虫的潜在耐药机制知之甚少。在这里，我们表明，莫能菌素导致积累的球虫弓形虫在一个明显的晚S期细胞周期检查点。此外，利用莫能菌素抗性T.弓形虫突变体的研究表明，莫能菌素的这种作用依赖于MutS DNA损伤修复酶（TgMSH-1）的线粒体同源物的功能。此外，相同的TgMSH-1依赖的细胞周期破坏观察到抗寄生离子载体盐霉素和DNA烷基化剂甲基亚硝基脲。我们的研究结果表明，莫能菌素和盐霉素对球虫寄生虫的作用模式的一种新机制，其中药物通过未知机制激活MSH-1依赖的细胞周期检查点，最终导致寄生虫死亡。这一模型表明，细胞周期的破坏是一个重要的介导剂的药物敏感性和耐药性的离子型抗生素的球虫寄生虫。
Monensin is a polyether ionophore antibiotic that is widely used in the control of coccidia in animals. Despite its significance in veterinary medicine, little is known about its mode of action and potential mechanisms of resistance in coccidian parasites. Here we show that monensin causes accumulation of the coccidian Toxoplasma gondii at an apparent late-S-phase cell cycle checkpoint. In addition, experiments utilizing a monensin-resistant T. gondii mutant show that this effect of monensin is dependent on the function of a mitochondrial homologue of the MutS DNA damage repair enzyme (TgMSH-1). Furthermore, the same TgMSH-1-dependent cell cycle disruption is observed with the antiparasitic ionophore salinomycin and the DNA alkylating agent methyl nitrosourea. Our results suggest a novel mechanism for the mode of action of monensin and salinomycin on coccidial parasites, in which the drug activates an MSH-1-dependent cell cycle checkpoint by an unknown mechanism, ultimately leading to the death of the parasite. This model would indicate that cell cycle disruption is an important mediator of drug susceptibility and resistance to ionophoric antibiotics in coccidian parasites.