The ClpP peptidase of Wolbachia endobacteria is a novel target for drug development against filarial infections.
The ClpP peptidase of Wolbachia endobacteria is a novel target for drug development against filarial infections.
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DOI：
10.1093/jac/dkt105
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发表时间：
2013-08
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通讯作者：
Andrea Schiefer;J. Vollmer;Christine Lämmer;S. Specht;Christian S. Lentz;H. Ruebsamen-Schaeff;H. Brötz-Oesterhelt;A. Hoerauf;K. Pfarr
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作者：
Andrea Schiefer;J. Vollmer;Christine Lämmer;S. Specht;Christian S. Lentz;H. Ruebsamen-Schaeff;H. Brötz-Oesterhelt;A. Hoerauf;K. Pfarr
背景技术 引起淋巴丝虫病或盘尾丝虫病（河盲症）的丝虫感染可以用针对必需的内共生沃尔巴克氏体细菌的抗生素（例如强力霉素）治疗。沃尔巴克氏体的消耗会抑制蠕虫的发育并导致蠕虫死亡。现有抗生素对儿童、孕妇或哺乳期妇女的使用有限制。因此，需要可以向所有人群提供且治疗时间较短的替代抗生素。酰基缩肽类抗生素已被证明可以通过过度激活肽酶 ClpP 来抑制细菌的生长。这类抗生素的新颖作用方式可以更快地杀死细胞内细菌。目的 表征酰基缩肽针对沃尔巴克氏菌 ClpP 的活性。方法 研究了酰基缩肽在体外昆虫细胞中对抗沃尔巴克氏体以及培养物中蠕虫的活性。此外，通过荧光显微镜和电子显微镜研究了结构效应。 ClpP 的活性也在体外进行了研究。结果 我们表明，酰基缩肽对体外昆虫细胞内的重组沃尔巴克氏体 ClpP 和内生细菌具有活性，并且一些衍生物对培养的丝虫也具有活性。经过治疗后，这些蠕虫变得无法活动并死亡，后者通过活力测定得到证实。结论 沃尔巴克氏体中酰基缩肽的作用方式是 ClpP 失调，导致蛋白质（包括细胞分裂蛋白 FtsZ）不受控制的降解。我们的结果表明，沃尔巴克氏菌 ClpP 是进一步发现抗丝虫抗生素的靶点。
BACKGROUND Filarial infections causing lymphatic filariasis or onchocerciasis (river blindness) can be treated with antibiotics (e.g. doxycycline) targeting the essential endosymbiotic Wolbachia bacteria. The depletion of Wolbachia inhibits worm development and causes worm death. Available antibiotics have restrictions for use in children and pregnant or breastfeeding women. Therefore, alternative antibiotics are needed that can be given to all members of the population and that are active with a shorter therapy time. Antibiotics of the acyldepsipeptide class have been shown to inhibit the growth of bacteria by overactivating the peptidase ClpP. The novel mode of action of this class of antibiotics could lead to faster killing of intracellular bacteria. OBJECTIVES To characterize acyldepsipeptide activity against the Wolbachia ClpP. METHODS The activity of acyldepsipeptides was investigated against Wolbachia in vitro in insect cells and also against worms in culture. In addition, structural effects were investigated by fluorescence microscopy and electron microscopy. The activity of ClpP was also investigated in vitro. RESULTS We show that acyldepsipeptides are active against recombinant Wolbachia ClpP and endobacteria resident within insect cells in vitro, and some derivatives were also active against filarial worms in culture. As a consequence of treatment, the worms became immotile and died, the latter confirmed by a viability assay. CONCLUSIONS The mode of action of the acyldepsipeptides in Wolbachia is the dysregulation of ClpP, causing the uncontrolled degradation of proteins, including the cell division protein FtsZ. Our results demonstrate that wolbachial ClpP is a target for further antifilarial antibiotic discovery.