PDF(Pubmed)
Abstract：
The interplay between humans and their microbiome is crucial for various physiological processes, including nutrient absorption, immune defense, and maintaining homeostasis. Microbiome alterations can directly contribute to diseases or heighten their likelihood. This relationship extends beyond humans; microbiota play vital roles in other organisms, including eukaryotic pathogens causing severe diseases. Notably, Wolbachia, a bacterial microbiota, is essential for parasitic worms responsible for lymphatic filariasis and onchocerciasis, devastating human illnesses. Given the lack of rapid cures for these infections and the limitations of current treatments, new drugs are imperative. Here, we disrupt Wolbachia\'s symbiosis with pathogens using boron-based compounds targeting an unprecedented Wolbachia enzyme, leucyl-tRNA synthetase (LeuRS), effectively inhibiting its growth. Through a compound demonstrating anti-Wolbachia efficacy in infected cells, we use biophysical experiments and x-ray crystallography to elucidate the mechanism behind Wolbachia LeuRS inhibition. We reveal that these compounds form adenosine-based adducts inhibiting protein synthesis. Overall, our study underscores the potential of disrupting key microbiota to control infections.
摘要：
人类与其微生物组之间的相互作用对于各种生理过程至关重要，包括营养吸收，免疫防御,保持体内平衡。微生物组改变可以直接导致疾病或增加其可能性。这种关系超越了人类；微生物群在其他生物体中起着至关重要的作用，包括引起严重疾病的真核病原体。值得注意的是,Wolbachia,细菌微生物群，对负责淋巴丝虫病和盘尾丝虫病的寄生虫至关重要，毁灭性的人类疾病。鉴于这些感染缺乏快速治愈方法和目前治疗方法的局限性，新药势在必行。这里,我们破坏了Wolbachia与病原体的共生，使用硼化合物靶向前所未有的Wolbachia酶，亮氨酰-tRNA合成酶（LeuRS），有效抑制其生长。通过一种在受感染细胞中证明抗沃尔巴克氏菌功效的化合物，我们使用生物物理实验和X射线晶体学来阐明WolbachiaLeuRS抑制背后的机制。我们发现这些化合物形成抑制蛋白质合成的基于腺苷的加合物。总的来说,我们的研究强调了破坏关键微生物群以控制感染的潜力.
