膜靶向的抗菌肽模拟物设计、合成及生物学评价

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.

“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。

按照项目书的研究计划，三年来考察了：1）赖氨酸等阳离子氨基酸、吡啶盐和二甲基季铵盐等亲水基团，2）单链烷烃、双链烷烃等疏水基团，3）二芳基醚，利奈唑胺碱骨架等因素，合成了五个系列共计129个抗菌肽模拟物；测试了上述化合物对标准菌株、耐药菌株的抗菌活性，对红细胞、哺乳动物细胞的毒性，杀菌动力学，细胞膜去极化等药物作用机制及体内药效。发现10个左右高活性（最低抑菌浓度MIC小于2 μg/mL）、低红细胞毒性（半数红细胞溶血浓度HC50大于800 μg/mL）的先导化合物，目前在此基础上进行进一步的结构优化和机制研究。.探索了多种金属beta内酰胺酶抑制剂，发展了开链吡啶羧酸，NOTA二硫代甲酸盐、开链二硫代甲酸盐等3个系列共计40余个金属beta内酰胺酶抑制剂；测试了在细胞水平、分子水平的活性，红细胞、哺乳动物细胞的毒性，杀菌动力学、计算机虚拟对接等，发现了多个化合物在细胞和分子水平具有良好的活性，同时毒性较小。.对课题组早期开展的治疗老年痴呆药物利斯的明的不对称合成、海洋天然产物Jaspine B衍生物合成及抗肿瘤活性、烯烃环氮化开环串联反应以及在做抗菌药物利奈唑胺衍生物发现的手性噻唑二硫酮合成新方法进行了完善。.三年来，以第一作者或者通讯作者发表论文13篇，其中中科院一区论文5篇，二区论文2篇，三区论文5篇，四区论文1篇。获得中国发明专利授权12项，其中第一发明人11项，第二发明人1项。