金黄色葡萄球菌毒力因子关键催化酶CrtN抑制剂的开发及其抗MRSA活性研究

There has been an explosion in the prevalence of antibiotic resistant Staphylococcus aureus (S. aureus) infections, which have emerged as serious, worldwide threat to public health. Existing research shows that staphyloxanthin of S. aureus can promote resistance to reactive oxygen species killing and is an important virulence factor for pigmented S. aureus. Staphyloxanthin biosynthesis needs six kinds of enzyme catalyzed reactions, in which CrtN (diapophytoene desaturases) is used three times continuously and regarded as a key catalytic enzyme for biosynthesis of staphyloxanthin. In our previous work, we have demonstrated naftifine hydrochloride, an FDA-approved antifungal drug, to be a good CrtN inhibitor against staphyloxanthin biosynthesis, and efficiently fight pigmented S. aureus infections in vivo. Considering the defect of poor oral bioavailability of CrtN inhibitors discovered previously by us, in this project, we will carry out elaborative structural optimization and SAR research, and try to address two issues: (1) remarkably improve oral bioavailability of CrtN inhibitors while retaining potent activities in vivo; (2) achieve the first CrtN-inhibitor complex crystal structure and provide the structural insights into the design of novel CrtN inhibitors. There is a high probability of this project yielding novel drug candidates that can block S. aureus virulence and uncovering potential drug target for combatting antibiotic resistance of MRSA.

抗生素对金黄色葡萄球菌(简称金葡菌)耐药现象逐步加剧，已成为日益严峻的全球公共卫生问题。已有研究表明金葡菌分泌的金黄色色素(简称色素)能帮助金葡菌逃避人体先天免疫系统产生的活性氧的杀灭，是决定金葡菌致病能力的关键毒力因子。色素合成通路共需6种酶的催化，其中CrtN(脱氢鲨烯去饱和酶)被连续使用三次，是色素合成的关键催化酶。本项目前期发现老药萘替芬及其衍生物通过靶向CrtN发挥抑制色素合成的作用，并表现出良好的体内抗(耐药)金葡菌的药效。考虑到前期发现的CrtN抑制剂口服生物利用度较差的缺陷，本项目拟进一步开展深入的结构优化研究，重点解决两个问题：(1)在保持强效体内药效的基础上，显著提高候选药物的口服生物利用度；(2)首次获得CrtN/抑制剂复合物晶体结构，为后续基于结构的理性设计奠定基础。本项目的顺利实施有望为靶向细菌毒力因子的抗耐药菌药物创制探索出新型药物作用靶点和新结构候选药物。

抗生素对金黄色葡萄球菌(简称金葡菌)耐药现象逐步加剧，已成为日益严峻的全球公共卫生问题。已有研究表明金葡菌分泌的金黄色色素(简称色素)能帮助金葡菌逃避人体先天免疫系统产生的活性氧的杀灭，是决定金葡菌致病能力的关键毒力因子。色素合成通路共需6种酶的催化，其中CrtN(脱氢鲨烯去饱和酶)被连续使用三次，是色素合成的关键催化酶。本项目前期发现“老药”萘替芬、及其衍生物通过靶向抑制CrtN，发挥抑制色素合成的作用，并表现出良好的体内抗(耐药)金葡菌的药效。考虑到前期发现的CrtN抑制剂口服生物利用度较差的缺陷，本项目开展深入的结构优化研究，设计合成了340个萘替芬新结构衍生物，包括6类苯并含氧杂环骨架、1类苯并吡咯骨架、1类苯并呋喃骨架；通过体外抗(耐药)金葡菌色素生成、靶标CrtN抑制、增强活性氧和全血杀伤(耐药)金葡菌活性、小鼠体内耐药菌Mu50(VISA/MRSA) 和NRS271(LRSA/MRSA)感染的药效评价，发现衍生物JX08626具有优秀的体内、外抗(耐药)金葡菌活性，显著优于(p < 0.01)两组阳性药：利奈唑胺和万古霉素。初步的成药性(药代、安评)评价，确证JX08626可以作为临床前候选药物PCC，并于2018年12月实现技术转化，转让合同金额为14000万人民币。本项目研究结果为靶向细菌毒力因子的抗耐药菌药物创制提供了新型药物靶标CrtN和新结构候选药物。