Belo Yael, Malach Einav, Hayouka Zvi
Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agricultural, Food & Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
Bioconjug Chem. 2024 Nov 20;35(11):1716-1722. doi: 10.1021/acs.bioconjchem.4c00291. Epub 2024 Oct 14.
The immune system plays a critical role in protecting the host against pathogens. However, mechanisms for evading the immune system have evolved in pathogens, altering their surface proteins or causing the expression of enzymes that interfere with the immune response. These strategies cause pathogens to escape detection and destruction by the immune system, thereby inducing severe infections. Thus, there is a critical need to develop new chemical tools to recruit the immune system against evading pathogens. Here, we describe a novel strategy for targeting pathogens, by labeling them with a chimeric agent that comprises a peptide bacterial binder, conjugated to an immune-protein tag that is recognizable by the complement system, thereby recruiting the immune system against the targeted pathogen. The chimeric tag was developed by conjugating the peptide bacterial binder with the C3b complement system activating protein. We showed that the chimeric C3b tag preserved its activity and was able to bind the C5 complement protein with strong binding affinity. Using this approach, we have demonstrated that the chimeric agent was able to eradicate 90% of complement-resistant bacterial cells. By showing enhancement of complement sensitivity in complement-resistant pathogens, this work demonstrates the basis for a new therapeutic approach for targeting pathogenic bacteria, which could open a new era in the development of selective and effective antimicrobial agents.
免疫系统在保护宿主抵御病原体方面发挥着关键作用。然而，病原体已经进化出逃避免疫系统的机制，改变其表面蛋白或导致干扰免疫反应的酶的表达。这些策略使病原体能够逃避免疫系统的检测和破坏，从而引发严重感染。因此，迫切需要开发新的化学工具来调动免疫系统对抗逃避的病原体。在此，我们描述了一种针对病原体的新策略，通过用一种嵌合剂标记它们，该嵌合剂包含一种肽类细菌结合剂，与补体系统可识别的免疫蛋白标签偶联，从而调动免疫系统对抗靶向病原体。该嵌合标签是通过将肽类细菌结合剂与C3b补体系统激活蛋白偶联而开发的。我们表明，嵌合C3b标签保留了其活性，并能够以强结合亲和力结合C5补体蛋白。使用这种方法，我们证明了嵌合剂能够根除90%的补体抗性细菌细胞。通过显示补体抗性病原体中补体敏感性的增强，这项工作证明了一种针对病原菌的新治疗方法的基础，这可能会开启选择性和有效抗菌剂开发的新纪元。
