作用于庚糖转移酶新靶标的贵州民族药用植物抗菌活性成分系统研究

Currently, infectious diseases are still the greatest potential threat of public health and safety worldwide. The emergence of multi-drug resistant bacteria becomes one of the greatest challenges of the twenty-fist century, which might lead to no clinical drug available in the future. Therefore, new anti-microbial agents with novel mechanism of action have become the hot topic. And more attentions have been paid to traditional Chinese medicine as well as folk medicine for the discovery of natural lead compounds. Recently, our group focuses on discovering natural leads with new antibiotic targets, and exploring novel specific enzymatic assay for antivirulence based on heptosyltransferase (WaaC), which is a key enzyme involved in the biosynthesis of the membrane of Gram-negative bacteria. And we found 4 natrual compounds showed potent inhibitory activity on WaaC. In this research, we scheduled to study around 30 ethnic medicinal herbs from Guizhou province with inhibitory activity against WaaC. Meanwhile, a systematic separation, purification and lead structural optimization study will be conducted for the crude extracts or effective fractions. in addition, the structure-activity relationship will be studied for the bioactive natural compounds or their derivatives. The objective is to obtain one or two drug candidates with potent inhibitory activity against WaaC, and the results of this study will pave the way for the further development of new anti-microbial agents from natural resources.

细菌感染性疾病在世界范围内依然是当前社会公共卫生安全的最大潜在威胁，多药耐药细菌的出现更可导致临床无有效药可用的困境。具有全新作用机制的抗菌剂研究已经成为当前药物研究的热点，而从我国丰富的中药、民族药资源中寻找新型抗菌先导化合物受到了越来越大的关注。本研究组近年来致力于中药民族药来源的具有抗毒力作用机制新型抗菌剂天然先导化合物的寻找，本项目前期曾针对新型抗毒力机制特异性酶靶标：革兰氏阴性菌庚糖转移酶（WaaC）进行了两种黔产药用植物的抑菌活性成分研究，并首次发现了4个天然来源的小分子化合物具有较好的WaaC抑制活性。通过本项目我们拟对30余种黔产抗感染药用植物粗提物进行细菌水平的抗毒力活性初步研究，并对具有较强抗毒力活性的粗提物或有效部位进行深入的成分分离及先导物结构衍生研究，同时结合基于WaaC的抗革兰氏阴性菌活性评价及构效关系分析，力争获得1-2个有抗菌新药开发潜力的候选药物分子。

细菌感染性疾病在世界范围内依然是当前社会公共卫生安全的最大潜在威胁，多药耐药细菌的出现更可导致临床无有效药可用的困境。具有全新作用机制的抗菌剂研究已经成为当前药物研究的热点，而从我国丰富的中药、民族药资源中寻找新型抗菌先导化合物受到了越来越大的关注。本研究组近年来致力于中药民族药来源的具有抗毒力作用机制新型抗菌剂天然先导化合物的寻找，通过本项目完成了31种黔产抗感染药用植物粗提物的细菌水平的抗毒力活性初步研究，并从其中的白及等五种植物粗提物中分离得到163个单体化合物，同时选择槲皮素及丹参酮为先导化合物进行了结构修饰研究，获得86个衍生物，并完成了其中大部分化合物的抗菌研究。此外，项目还对来源于白及中的联苄类化合物进行了全合成研究。