抗MRSA活性rhodomyrtosone B类似物的合成和构效关系研究

MRSA作为易感染的重要病原菌之一，其感染已与乙型肝炎、艾滋病并列为当今世界三大最难解决的感染性疾病。自药用植物桃金娘中分离的rhodomyrtosone B具有显著的抗MRSA活性，它的活性与万古霉素相当，并且起效更快，对万古霉素耐药菌也仍然有效。本项目前期研究发现，改变rhodomyrtosone B中的间苯三酚片段能得到活性更好的类似物，其中以开环的二酰基类似物活性最好。特别是二戊酰基类似物KTC4，其活性优于万古霉素16倍。为进一步改善它的成药性缺陷，本项目拟在前期研究基础上，设计合成一系列专一性强、活性高、更具临床应用价值的类似物；并评价不同结构类似物对MRSA的抑制活性，对其构效关系进行深入的研究；为开发具有自主知识产权、高效低毒、机制新颖的抗MRSA感染药物提供科学依据和理论基础。

Methicillin-resistant Staphylococcus aureus (MRSA) is a predominant pathogen in patients suffering from nosocomial infections. Its infection has been considered as three of the most intractable infectious diseases with hepatitis B and AIDS. Rhodomyrtosone B which was isolated from the leaves of Rhodomyrtus tomentosa, has similar anti-MRSA activity as vancomycin. It was also exhibited pronounced antibacterial activity against other antibiotic-resistant pathogens including vancomycin-intermediate Staphylococcus aureus and vancomycin-resistant enterococcal strains. In the preliminary study towards the structure-activity relationships of rhodomyrtosone B, we discovered that more active analogues could be achieved when the acylphloroglucinol fragment was changed. The ring-opening diacylphloroglucinol analogues are usually the most active ones, especially KTC4, its anti-MRSA activity was 16 times more than that of vancomycin. In order to further improve the druggability of rhodomyrtosone B, a series of analogues would be conducted to optimize its structure in this program. Moreover, the biological activity screening and structure-activity relationships study of these analogues would be accessed to some novel antibiotic candidates with high efficiency, low toxicity, novel mechanism and independent intellectual property rights.