整合金属蛋白质组学和代谢组学方法对镓抗菌剂作用机理的系统性分析

The unprecedented emergence of antibiotic-resistant pathogens and the running out of antibiotics pipeline have posed a great threat to public health. Gallium compounds have shown great potential in fighting against bacterial infection, either being used alone or as antibiotics adjuvants. Although gallium-based antimicrobials have entered into clinical trial II for the treatment of lung infection of patients with cystic fibrosis, the exact toxic mechanisms of gallium in the infectious bacteria remain largely unknown. In this project, we will integrate high-throughput metalloproteomic and metabolomic approaches for the systematic identification of gallium-associated proteins/peptides and gallium-induced metabolic changes in both P. aeruginosa PAO1 and B. cenocepacia J2315, with the aim of understanding the primary target proteins and pathways of antimicrobial gallium. We expect the combined metalloproteomic-metabolomic study will provide novel insights into the systematic responses of bacteria under gallium stress, as well as a theoretical basis for the clinical application of gallium drugs. The newly identified gallium-associated proteins will also serve as a rich resource for the development of new gallium-based antimicrobials.

随着抗生素的广泛使用，细菌的耐药性问题变得日趋严重。镓化合物单独或与抗生素联用在治疗细菌感染方面表现出巨大潜力,且镓类抗菌剂用于治疗囊性纤维化患者慢性肺部感染已进入临床研究阶段。然而目前对于镓化合物的具体抗菌作用机制尚未明确。本项目拟综合利用金属蛋白质组学和代谢组学研究方法，针对镓化合物在绿脓杆菌和洋葱伯克霍尔德菌中的结合蛋白、肽段及诱导产生代谢物变化等问题开展研究，目标是对镓化合物在细菌内的关联生物靶点进行全面鉴定，对镓化合物的主要作用通路及关键靶点蛋白进行系统性分析识别，并通过金属蛋白质组学和代谢组学鉴定结果的对应关系，揭示镓化合物抑制两类细菌生长的作用机制。此研究的开展将为镓类药物的临床研究奠定基础，也为进一步提高镓类药物的药效以及新型镓类药物的研发提供理论指导。

随着抗生素的广泛使用，细菌的耐药性问题变得日趋严重。抗菌金属离子单独或与抗生素联用，在治疗细菌感染方面表现出巨大潜力。本项目综合利用金属蛋白质组学及代谢组学研究方法，针对镓离子对抗绿脓杆菌、铋剂对抗幽门螺杆菌的作用机制进行了系统性的分析，鉴定出镓离子在绿脓杆菌内的重要作用靶点蛋白，并首次揭示通过外加代谢物改变细菌的代谢状态，以提高镓离子抗菌活性的新型抗菌策略。此研究为新型金属药物的研发提供理论基础。