“超级细菌”的出现和蔓延严重威胁临床抗感染治疗。抗菌肽对多种耐药的“超级细菌”具有良好的活性，目前已有15个抗菌肽进入临床阶段，但是其存在酶稳定性差、生产成本高等不足。抗菌肽模拟物是抗菌肽的小分子模拟物，是近年来研究的热点，目前有2个药物进入临床。. 本课题组前期研究发现查尔酮抗菌肽模拟物具有良好的抗菌活性，特别是对于多类多重耐药菌均表现出良好的体外抗菌活性。本项目以骨架片段库和基于结构的合理药物设计为导向，以细菌膜为靶点，进一步以活性基团尤其是在临床应用广泛的抗生素为骨架，考察亲水基团与疏水基团的平衡等因素，设计合成4个系列抗菌肽模拟物。通过体外药效实验测试抗菌活性；通过红细胞溶血、细胞毒性评价毒性；对活性高毒性小的化合物，开展抗菌作用机制研究。预期能2-3个发现针对“超级细菌”有效的新型抗生素先导物，为进一步的结构修饰及成药性开发奠定基础。

The emergence and spread of "superbug" is a serious threat to clinical anti-infection treatment. Antimicrobial peptides (AMPs) have shown some most promise as potential antibiotics against “superbug”. 15 of them are undergoing clinical trials. AMPs are mainly limited by their lability towards proteases, and their high cost of manufacture. Antimicrobial peptides mimics (AMPM) as the mimics of AMPs has attracted considerable interest from medicinal chemist and two of them are undergoing clinical trials.. Chalcone AMPM were found to have good activity especially for many multiple drug-resistance bacteria in our early study. Based on skeletal fragment library and structure-based drug design, bacterial membrane was selected as target. Many factors such as active functional group especial traditional clinical antibiotic, hydrophilic functional group, lipophilic functional group will be considered. Four series of AMPM will be designed and synthesized. In vitro pharmacodynamics of these compounds will be investigated. The toxicity of AMPM will be evaluated by toxicity towards erythrocytes and human cells. The antibacterial mechanism for selected promising compounds will be studied. It is hoped that we can find two or three potent and broad-spectrum leading compound for “superbug”. This study will lay a good foundation for further structure modification and study.