新型融合肽DRS-DP-2抗耐甲氧西林金黄色葡萄球菌的多重效应及机制研究

耐甲氧西林金黄色葡萄球菌（MRSA）具有广泛耐药性且耐药机制复杂，现有抗生素已不能满足临床需求，急需发现新型抗菌药物。申请人前期发现两条全新序列的多肽，合理设计得到具有快速杀菌、抗生物被膜及逆转耐药特点，同时体内活性较佳的新型融合肽DRS-DP-2。进一步研究发现其可促进细胞内容物释放、可同时定位于细胞膜和胞内、可与基因组DNA结合，并降低sarA及mecA基因的表达。本项目拟深入探讨其抗MRSA的多重作用机制，考察其对细胞膜、生物代谢及细胞壁的影响明确其膜损伤及胞内调控机制，基于sarA及mecA通路探索其抗生物被膜及逆转耐药的作用机制，随后构建sarA及mecA敲除株及回补株进行验证，最终体内明确其多重抗MRSA机制，从分子、细胞和动物水平阐明DRS-DP-2的多重抗MRSA机制，为新型抗MRSA药物的开发奠定基础。

Due to the extensive drug resistance and its complex mechanism of methicillin-resistant staphylococcus aureus (MRSA), traditional antibiotics can no longer meet the clinical needs. Therefore, novel antibacterial agents are urgently needed to be discovered. Our preliminary study found two novel antimicrobial peptides. Rational design of the peptides led the discovery of the novel fusion peptide, DRS-DP-2, with the characteristics of rapid sterilization, anti-biofilm and reverse drug resistance of MRSA, as well as the excellent in vivo activity. Further research found that it could promote the release of MRSA cell contents, can be localized on the cell membrane and intracellularly, can bind to MRSA genomic DNA, and reduce the expression of sarA and mecA genes. This study intends to explore the multiple mechanisms of DRS-DP-2 against MRSA. Its membrane damage and intracellular regulatory mechanism will be investigated on the cell membrane, biological metabolism, and cell wall. The anti-biofilm mechanism will be revealed based on sarA regulatory pathways. The mechanism of reversing MRSA resistance will be explored based on the mecA regulatory pathways. Then, sarA and mecA knockout and complemented strains will be estalished to vertify the mechanisms. Finally, the anti-MRSA mechanisms will be vertified in vivo through mouse model. The multiple anti-MRSA mechanism of DRS-DP-2 will be clarified from the molecular, cell and animal level, which will lay the foundation for the development of novel anti-MRSA drugs.