红果仔间苯三酚类成分抗耐药菌感染的构效关系和作用机制研究

Drug-resistant bacterial infection is a major threat to global public health. Thus, it is extremely urgent to investigate and develop anti-bacterial infection drugs with novel mechanisms. Virulence factors are related genes or proteins in the components or regulatory mechanisms affecting bacterial virulence. Bacterial virulence factors regulate multiple processes in the process of bacterial infection. Virulence inhibitors aimed at inhibiting bacterial virulence factors can treat bacterial infections by inhibiting the expression or function of bacterial virulence factors, quorum sensing, and adhesion. Virulence inhibitors are safer to the host and may impose weaker selective pressure for the development of antibiotic resistance relative to current antibiotics. Therefore, targeting bacterial virulence factors is a new strategy for the study of anti-bacterial infection drugs. In our previous study of antimicrobial agents from Eugenia uniflora L. (Myrtaceae), several phloroglucinol derivatives with anti-methicillin-resistant Staphylococcus aureus (MRSA) infection activities were obtained. Further, we found that these components exert anti-MRSA infection activity by acting on the virulence related protein--clumping factor of S. aureus. However, the mechanisms of action and structure-activity relationships of these active compounds remain to be explored. Based on the preliminary work, this project plans to systematically investigate the phloroglucinol constitutes of Eugenia uniflora and evaluate their anti-drug-resistant bacterial infection activities. Additionally, the mechanisms of action and structure-activity relationships of these active compounds will also be studied. Our study will provide scientific basis for the development of new antimicrobial infection drugs.

耐药菌感染是威胁全球公共健康的重大问题，开发新型抗耐药菌感染药物迫在眉睫。细菌毒力因子是影响细菌毒力的组成成分及调控机制中的相关基因或蛋白，参与调控细菌感染过程的多个环节。细菌毒力因子抑制剂通过抑制细菌毒力因子的表达或功能、群体感应及黏附等途径发挥作用，不仅能够安全有效的治疗细菌感染而且不易产生耐药，是新型抗耐药菌感染药物研究的重要途径和方向。本课题组在前期研究中首次发现红果仔中的新型间苯三酚倍半萜杂合物类成分具有显著抗耐甲氧西林金葡菌感染作用，并进一步证实该类成分通过作用于金葡菌凝聚因子（与黏附相关的毒力因子）而发挥作用。然而，该类成分抑制金葡菌凝聚因子的构效关系和作用机制有待深入探索。本项目拟在前期工作基础上，进一步对红果仔中的间苯三酚倍半萜杂合物类成分进行系统分离和鉴定，评价它们的抗耐药菌感染作用，并研究其构效关系和作用机制，为开发新型抗耐药菌感染药物提供科学依据。

耐药菌感染是威胁全球公共健康的重大问题，开发新型抗耐药菌感染药物迫在眉睫。细菌毒力因子是影响细菌毒力的组成成分及调控机制中的相关基因或蛋白，参与调控细菌感染过程的多个环节。细菌毒力因子抑制剂通过抑制细菌毒力因子的表达或功能、群体感应及黏附等途径发挥作用，不仅能够安全有效的治疗细菌感染而且不易产生耐药，是新型抗耐药菌感染药物研究的重要途径和方向。本课题组在前期研究中首次发现红果仔中的新型间苯三酚倍半萜杂合物类成分具有显著抗耐甲氧西林金葡菌感染作用，并进一步证实该类成分通过作用于金葡菌凝聚因子（与黏附相关的毒力因子）而发挥作用。然而，该类成分抑制金葡菌凝聚因子的构效关系和作用机制有待深入探索。本项目对红果仔中的间苯三酚倍半萜杂合物类成分进行系统分离和结构鉴定，共获得56个化合物，包括32个新化合物，12个新骨架化合物；通过评价所得化合物的抗耐药菌作用，发现化合物EUF-1~EUF-4、EUF-17~EUF-23、EUF-24、EUF-34~EUF-35具有显著抗耐药菌活性并阐明该类化合物的构效关系；进一步的作用机制研究表明，活性化合物通过抑制金葡菌凝聚因子发挥抗耐药菌作用。本项目研究有望发现新机制的抗菌药物，为研制开发新型抗耐药菌药物提供了科学依据。