新型天然抗MRSA先导化合物的发现、结构优化及作用机制研究

MRSA感染已与乙肝、艾滋病并列为当今世界三大最难解决的感染性疾病。本项目前期从红千层和千层金中发现了一系列结构新颖的抗MRSA活性先导化合物，部分化合物活性接近万古霉素。药理机制表明有别于万古霉素，它们通过细胞膜去极化导致MRSA致死，并呈现出广谱快速、不耐药的特性。为进一步丰富抗MRSA化合物的结构类型并改善它们的成药特性，开发具有独立自主产权、高效低毒、机制新颖的抗MRSA药物分子。本项目拟在前期基础上，进一步开展具有抗MRSA活性的澳洲引种桃金娘科植物红千层、千层金、美丽薄子木以及茴香桃金娘中活性先导化合物的发掘。同时，通过多样性全合成的手段对先导化合物进行结构修饰与优化，合成一系列活性高、更具临床应用价值的类似物；在形态与分子水平上阐明活性化合物抗MRSA的分子机理和作用靶点，并揭示其构效关系。为开发具有自主知识产权、高效低毒、机制新颖的MRSA感染药物提供科学依据和理论依据。

Methicillin-resistant Staphylococcus aureus (MRSA) is well known as a predominant pathogen in patients suffering from nosocomial infections. Its infection along with hepatitis B and AIDS have been considered as the three most intractable infectious diseases for the whole word. Our previous phytochemical study on the leaves of Callistemon viminalis and Melaleuca bracteata had resulted in the isolation of a serious of active anti-MRSA lead compounds with novel structure or unprecedented skeleton. Many of them exhibit significant anti-MRSA activity, which is similar as that of vancomycin. The preliminary mechanism study had shown that the lead compounds acted rapidly as a bactericidal agent by disturbing the bacterial membrane potential without causing membrane disruption, representing a very promising bactericidal candidate with mechanism differing from other antibiotic agents available either in the clinic or in development. Encouraged by the previous promising achievements, the current project will perform extensive phytochemical study on Callistemon viminalis, Melaleuca bracteata, Leptospermum brachyandrum, Backhousia anisate to rapidly identify anti-MRSA lead compounds, and optimize their structure as well as their druggability with the aid of diversity-oriented total synthesis. Besides, the analysis of their structure-activity relationship and elucidation of their molecular mechanism underlying the antimicrobial activity will be conducted to access some novel antibiotic candidates with high efficiency, low toxicity, novel mechanism and independent intellectual property rights. Our study will also provide the scientific basis for the efficient development of novel anti-MRSA agents.