影响扬子鳄来源α-螺旋型抗菌肽杀菌速度的结构参数和机理研究

抗菌肽（AMPs）在鳄类动物免疫系统中的功能尚不十分清楚。AMPs作为一类具有开发潜力的抗耐药菌感染药物先导分子，杀菌速度快是其重要优势之一和不易导致微生物耐药的重要原因之一，但迄今为止影响AMPs杀菌速度的结构参数和机理仍然未知。我们前期从扬子鳄体内发现2种α-螺旋型AMPs具有广谱抗菌活性但杀菌速度差异巨大，为AMPs杀菌速度相关研究提供了很好的切入点。本项目拟首先通过构效关系研究明确影响α-螺旋型AMPs杀菌速度的结构参数；进一步从结合细菌表面结构和破坏细菌细胞膜两方面揭示相关结构参数影响AMPs杀菌速度的机理；最后构建动物模型比较不同杀菌速度的AMPs对耐药菌感染的治疗效果和诱导细菌耐药性产生的能力差异。通过本项目，期望揭示不同杀菌速度的AMPs在扬子鳄抗感染免疫反应中的功能差异，加深我们对扬子鳄免疫系统的认识，并为开发起效快、不易引起耐药的抗耐药菌感染药物提供分子模板和理论支持。

The function of antimicrobial peptides (AMPs) in the immune system of crocodiles is not fully understood. AMPs, as a type of potential drug lead molecules against drug-resistant infections, possess rapid sterilization speed, which is one of their important advantages, and one of the important reasons that why they unlikely induce microbial resistance. However, the structural parameters and mechanism that affect the AMPs’ sterilization speed so far remain unknown. Previously we identified two α-helical AMPs from Alligator sinensis possessing broad-spectrum antimicrobial activity, but different sterilization speed, which provided a good starting point for AMPs sterilization speed related study. The present project firstly intends to determine the structural parameters that affect the sterilization speed of α-helical AMPs through structure-activity relationship studies; then reveals the mechanism of the relevant structural parameters affecting the sterilization speed of α-helical AMPs from the aspects of combining with the surface structure of bacteria and destroying the bacterial cell membrane; and finally constructs animal infection models to compare the in vivo anti-infective efficacy of AMPs with different sterilization speed and their ability in inducing bacterial resistance. Through this project, we hope to reveal the functional differences of AMPs with different sterilization speed in the anti-infective immune responses of Alligator sinensis, deepen our understanding of the immune system of Alligator sinensis, and provide templates and theoretical supports for the development of anti-infective peptide drugs with rapid effect and less possibility of inducing drug resistance.