抗菌肽Jelleine-I与CRISPRa技术联用靶向目标病原菌的抗菌作用研究

抗菌肽是一种有潜力发展成为新型抗菌药物的小分子多肽，具有良好的抗菌活性且不易产生耐药性。但同其他抗菌剂一样，抗菌肽也无法区分具体的杀菌对象，长期使用会导致菌群失衡。我们前期研究发现：抗菌肽Jelleine-I具有高效的抗菌活性，是一种理想的抗菌肽的先导化合物。为了增加Jelleine-I抗菌作用的靶向性，本课题拟将Jelleine-I与可精确调控基因表达的CRISPRa技术联用，通过利用CRISPRa技术靶向激活目标细菌Abc1表达，诱导膜内磷脂酰丝氨酸暴露于外侧以增加目标细菌表面带负电荷基团并增加膜通透性，然后以静电作用吸附更多阳离子肽Jelleine-I锚定于细菌表面并通过破坏细胞膜发挥抗菌作用。本课题将利用细菌及动物模型深入探究Jelleine-I与CRISPRa技术联用对目标细菌的靶向抗菌作用和对小鼠感染模型的治疗效果并阐明其具体的抗菌机制，以期为病原菌感染的精准治疗提供新的思路。

Antimicrobial peptides are lead compounds that have the potential to replace traditional antibiotics as new antimicrobial agents. However, like other antibacterial agents, they can not distinguish the specific target of antimicrobial effect, long-term use will lead to imbalance of bacteria. Our previous study found that the antimicrobial peptide Jelleine-I has high antibacterial activity, but it also lacks the selectivity of antibacterial objects. In order to increase the targeted antibacterial activity, Jelleine-I will combine with CRISPRa technology which can be used to regulate gene expression. Through the use of CRISPRa technology targeted Abc1, activation of target bacteria induced phosphatidylserine exposed to the outside in order to increase in the surface of negatively charged groups and increased membrane permeability, and then to adsorb more cationic Jelleine-I to destroy cell membranes of bacteria. This project will use bacteria and animal models to explore the targeted antibacterial effect of Jelleine-I combined with CRISPRa on target bacteria and the therapeutic effect on mouse infection model, and clarify the antibacterial mechanism. The project will provide new ideas for the precise treatment of pathogen infections.