抗金黄色葡萄球菌毒力的小分子化合物及其作用分子机制研究

项目名称： 抗金黄色葡萄球菌毒力的小分子化合物及其作用分子机制研究

项目编号： No.21472207

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 环境科学、安全科学

项目作者： 蓝乐夫

作者单位： 中国科学院上海药物研究所

项目金额： 86万元

中文摘要： 细菌的耐药性已经成为日益严峻的全球公共卫生问题，我们亟需发现新型的药物作用靶点和新型的抗细菌感染药物。目前，抗细菌毒力的药物正在成为新型抗细菌感染药物研究的热点。具有甲氧西林耐药性的金黄色葡萄球菌（简称金葡菌），被公认是超级细菌，严重危害人类生命健康。已有的研究发现金葡菌的金黄色色素合成途径是新的、潜在的药物作用靶点。在前期的研究中我们发现已上市药物（老药）LJ-188能有效抑制金葡菌的金黄色色素的生成，其半数有效抑制浓度IC50为280nM；进一步的动物实验表明LJ-188可显著地抑制金葡菌对小鼠的致病能力。在本项目中我们拟以LJ-188为小分子探针，研究其抑制金葡菌金黄色色素的产生、消减金葡菌致病力的分子机理，发现其作用靶点；进一步基于探针分子LJ-188开展小分子探针的结构优化研究。该项目的顺利实施将发现新型的抗金黄色葡萄球菌毒力的候选靶点及候选药物。

中文关键词： 金黄色葡萄球菌；抗毒力；小分子化合物；分子机制；靶点

英文摘要： We are now entering the post-antibiotic era. The increasing prevalence of bacterial strains involving so-called superbugs such as MRSA (Methicillin-resistant Staphylococcus aureus) demands the discovery of new drugs. Targeting bacterial virulence rather than bacterial growth represents a new paradigm to antimicrobial therapy that offers promising opportunities to prevent and treat infectious diseases. In S. aureus, staphyloxanthin has been shown to be a good target for drug design and therapeutic intervention. In our previous study, we found that the old drug LJ-188 blocks the staphyloxanthin biosynthesis in vitro, with a median inhibitory concentration (IC50) value of 280 nM. Further, LJ-188 treatment prolonged the survival of mice with lethal S. aureus challenge and reduced bacterial burden both in kidney and in heart significantly. In the proposed studies here, we will investigate the molecular mechanisms and the target(s) of LJ-188 in S. aureus. We will improve the features of LJ-188 to gain the lead compound which has a novel structure as well as improved biological activities. There is a high probability of this project yielding lead compounds that can inhibit S. aureus virulence and uncovering potential drug target to to design novel anti-infective drugs.

英文关键词： Staphylococcus aureus;Anti-virulence;Small molecule;Molecular mechanism;Target