Novel benzothiazole derivatives target the Gac/Rsm two-component system as antibacterial synergists against Pseudomonas aeruginosa infections  

作　　者：Jun Liu Wenfu Wu Jiayi Hu Siyu Zhao Yiqun Chang Qiuxian Chen Yujie Li Jie Tang Zhenmeng Zhang Xiao Wu Shumeng Jiao Haichuan Xiao Qiang Zhang Jiarui Du Jianfu Zhao Kaihe Ye Meiyan Huang Jun Xu Haibo Zhou Junxia Zheng Pinghua Sun 

机构地区：[1]State Key Laboratory of Bioactive Molecules and Druggability Assessment,College of Pharmacy,Jinan University,Guangzhou 510632,China [2]Key Laboratory of Xinjiang Phytomedicine Resource and Utilization,Ministry of Education,School of Pharmacy,Shihezi University,Shihezi 832003,China [3]School of Biomedical and Pharmaceutical Sciences,Guangdong University of Technology,Guangzhou 510006,China [4]Department of Oncology,the First Affiliated Hospital of Jinan University Guangzhou,Guangzhou 510632,China [5]Faculty of Medicine and Health,the University of Sydney,Sydney NSW 2006,Australia

出　　处：《Acta Pharmaceutica Sinica B》2024年第11期4934-4961,共28页药学学报（英文版）

基　　金：National Natural Science Foundation of China(No.22177039 and 82304274);National Key R&D Program of China(No.2021YFC2300400);China Postdoctoral Science Foundation(No.55350658).

摘　　要：The management of antibiotic-resistant, bacterial biofilm infections in skin wounds poses an increasingly challenging clinical scenario. Pseudomonas aeruginosa infection is difficult to eradicate because of biofilm formation and antibiotic resistance. In this study, we identified a new benzothiazole derivative compound, SN12 (IC_(50)= 43.3 nmol/L), demonstrating remarkable biofilm inhibition at nanomolar concentrations in vitro. In further activity assays and mechanistic studies, we formulated an unconventional strategy for combating P. aeruginosa-derived infections by targeting the two-component (Gac/Rsm) system. Furthermore, SN12 slowed the development of ciprofloxacin and tobramycin resistance. By using murine skin wound infection models, we observed that SN12 significantly augmented the antibacterial effects of three widely used antibiotics—tobramycin (100-fold), vancomycin (200-fold), and ciprofloxacin (1000-fold)—compared with single-dose antibiotic treatments for P. aeruginosa infection in vivo. The findings of this study suggest the potential of SN12 as a promising antibacterial synergist, highlighting the effectiveness of targeting the two-component system in treating challenging bacterial biofilm infections in humans.

关 键 词：Pseudomonas aeruginosa BIOFILM Antibioticresistant Two-component system Antibacterial synergist 

分 类 号：R97[医药卫生—药品]