针对严重的耐药细菌感染问题，进行天然蛋白（Cathelicidin 家族）来源抗菌肽结构优化，根据理化参数和体内/外活性，评价抗菌肽构效关系，获得高效、低毒、稳定的新型多肽分子。基于细菌细胞膜（或膜LPS）、耐药基因（质粒编码）、调节基因（调控RNAP关键因子δ70的ropD基因）和耐药相关蛋白的mRNA等靶点，借助本室构建的重组E. coli BL21 (DE3)-NDM-1（超级细菌）细胞/小鼠感染模型及多肽-寡核苷酸缀合物分子靶向递药体系等关键技术，阐明多肽对耐药细菌作用的多靶点分子机制。针对细菌感染性炎症，基于NADPH氧化酶p47-Phox的SH3结构域及泛素-蛋白酶通路IκBa亚基靶点，通过LTA/LPS诱导的细胞/动物炎症模型，揭示多肽对NADPH氧化酶复合体及NF-κB信号通路的影响。通过阐明多肽的构效关系、感染与炎症、多靶点，为多肽抗耐药细菌感染的临床应用奠定基础。

In view of the serious infection induced by drug-resistant bacteria, the structure of peptides derived from natural protein was improved. To get new peptide molecules with high activity and stability and low toxicity, the structure-activity relationship of these optimized peptides were evaluated based on their physicochemical properties and anti-microbial activity in vitro/in vivo. . To clarify the multiple targets mechanism of peptides against drug-resistant bacteria, the NDM-1 carrying bacteria (recombinant E. coli BL21 (DE3)-NDM-1,” superbugs”) infected cell/animal models and the molecular targeted drug delivery system mediated by peptide-oligonucleotide conjugates were used. The involved targets include bacterial membrane (or LPS), drug-resistant gene (encoded by plasmid), regulator gene (ropD which regulate the DNA-dependent RNA polymerase (RNAP) primary sigma factor 70 (δ70)) and mRNA (which regulate the translation of drug resistant-related proteins). . Meanwhile, for bacterial inflammation, the cell and animal inflammation models were stimulated by lipopolysaccharide (LPS) and lipoteichoic acid (LTA) to reveal the molecular mechanisms of interaction between peptides and NAPDH oxidase complex and/or the IKK-IκB-NF-κB signaling pathway. The involved targets include NADPH oxidase p47-Phox (C-terminal SH3 domain) and IκBa subunits predominated by ubiquitin-proteasome pathway.. It can provide a theoretical foundation for the clinical application of peptides against drug-resistant bacterial infection by illuminating the structure-activity relationship, antibacterial and anti-inflammatory molecular mechanisms and multiple targets effect of peptides.