新型季铵盐类抗菌肽模拟物的设计合成、抗MRSA活性及作用机制研究

抗MRSA新分子的发现对解决当前的“抗生素危机”问题具有关键性作用。小分子抗菌肽模拟物杀菌效果好、不易产生耐药且能改善天然抗菌肽毒性大、不稳定性及成本高昂等缺陷，有望为新型抗菌药物的开发提供新策略。前期通过对canthin-6-one类化合物的抗菌活性研究，我们发现了结构简单、毒性低且抗MRSA活性强的先导分子JC2。本项目拟在此工作基础上开展以下研究：（1）以化合物JC2为支架，设计合成两类小分子季铵盐抗菌肽模拟物，研究其构效关系和构毒关系，并发现高活、低毒、杀菌迅速、不易产生耐药且体内稳定的抗MRSA新分子；（2）从菌落水平、细胞水平和分子水平三方面分别研究该类分子对生物膜的形成影响和破坏作用、膜靶向作用及胞内的通路干预和调控作用。通过该项研究，有望得到作用机制较明确的抗MRSA新分子，为具有自主知识产权的新型抗菌药物创制提供思路，为解决当前的“抗生素危机”问题提供更多的选择。

The discovery of novel anti-MRSA molecules plays a key role in solving the current antibiotic crisis issue. Small molecular antibacterial peptide mimics have good bactericidal effects, and are not easy to generate drug resistance. Moreover, they could improve the shortcomings of natural antibacterial peptides such as high toxicity, instability and high cost. Therefore, they are expected to provide a new strategy for the development of novel antibacterial drugs. The leading compound JC2 with a simple structure, low toxicity and strong anti-MRSA activity, was found through our early antibacterial activity study of canthin-6-one analogues. This project intends to be carried out the following study based on our preliminary work. (1) Two classes of small molecular quaternary ammonium antibacterial peptide mimics will be designed and synthesized with compound JC2 as the scaffold. Then the structure‒activity and structure‒toxicity relationships will be investigated, and the novel anti-MRSA molecules with the properties of high activity, low toxicity, rapid sterilization, resistance to drug resistance and stability in vivo will be discovered. (2) The effects of these molecules on the formation and destruction of biofilms, the membrane targeting mechanism, and the intervention and regulation mechanism for intracellular pathway will be studied from three aspects: colony level, cell level and molecular level, respectively. It is expected to obtain some novel anti-MRSA molecules with clearer antibacterial mechanisms througn this study, which will provide ideas for the creation of new antibacterial drugs with independent intellectual property rights and provide more options for solving the current antibiotic crisis issue.