日益流行的多药耐药病原菌严重威胁人类生命安全。目前，已有病原菌对万古霉素、甲氧西林、碳青霉烯类抗生素耐药，一旦这些病原菌大范围流行，人类将将面临无药可用的窘境。因此，亟需发展作用机制新颖，不易引起耐药的新型药物。抗菌肽大多通过破坏细胞膜完整性杀菌而引起了广泛关注。本项目拟通过非天然氨基酸替换、D-逆肽改造、类肽修饰、引入新型侧链基团、聚合化或局部环化等对天然小分子抗菌肽polybia-MPI进行修饰改造，致力于提高其抗菌活性、生物稳定性和生物利用度；通过体内外抗菌（含临床耐药病原菌）活性研究及野生菌对药物敏感性变迁的研究，探讨polybia-MPI类似物在治疗耐药菌引起的感染的临床应用潜力; 通过膜-肽相互作用、波谱分析结合分子动力学模拟等研究探讨构效关系，阐明作用机制。本项目的开展将为抗菌肽的临床应用、发展不易耐药的、以细胞膜为靶标的新型抗菌药物提供思路和研究基础，具有重要的临床意义。

With the extensive use of antibiotics, there are frequent emergence of the resistant bacteria. What even worse, there are few active agents available for treating serious infections, since the prevalence of carbapenem-resistant and vancocin-resistant bacteria is increasing. Carbopenems and vancocin were thought to be the "last line" treatment agents available at present. New agents with novel action mode were urgently needed than ever before.It is now widely accepted that antimicrobial peptides (AMPs) could be promising alternatives to conventional antibiotics. AMPs target at the cell membrane, which is a thin and structured bilayer of phospholipid and protein molecules that envelopes the cell.So it was thought that AMPs were not affected by conventional multidrug resistant mechanism and it was difficult to develop resistance to it. Polybia-MPI was a short cationic α-helical amphiphilic antimicrobial peptide. In our study, a series of polybia-MPI derivatives were designed and synthsized to improve the antimicrobial activity, the stability in vivo and bioavailability by chemical modification, such as unnatural amino acid subtitution, inersion of D-amino acid, polymerization and partial cyclization. The in vitro and in vivo antimicrobial activity of all the derivatives against both the wild type bacteria and clinially isolated resistant bacteria will be studied. The results will be used to evaluate the clinical application potential of antimicrobial peptide. The spectrum analysis and molecular dynamics simulation will be employed to study the peptide-membrane interaction and structure-activity relationship, in order to further clarify the exact mechanism of antimicrobial peptide.So with the increasing resistance to conventional antibiotics, there is no doubt that the present study could offer a new strategy and some excellent alternatives to conventional antibiotics to defend the resistant bacteria.