抗生素耐药性的增加急需新的治疗手段来对抗细菌感染。细菌生物膜抑制剂被认为是克服细菌对抗生素耐药的有效策略之一；同时研究发现铁螯合剂可以加速耐药菌引起的慢性伤口的愈合，提示螯合铁可有效对抗细菌耐药。本课题组前期以铜绿假单胞菌信号分子PQS为模板设计其类似物羟基吡啶酮类化合物，发现这种具有铁螯合作用的化合物可以有效抑制铜绿假单胞菌生物膜形成。由于PQS兼具群体感应和铁载体通路调控作用，我们提出发展以PqsR为靶标的兼具细菌群体感应调节及铁螯合作用的双效分子可能是细菌生物膜抑制剂的有效药物设计策略。为验证此假说，本项目拟进一步设计合成系列新型的羟基吡啶酮类衍生物，研究其抗细菌生物膜构效关系，发现新药苗头化合物；研究其对于PqsR群体感应信号通路及铁载体信号通路的调节作用；通过靶标垂钓技术探索或验证其作用的信号通路靶标；为基于细菌信号通路双重抑制策略的新型铜绿假单胞菌生物膜抑制剂研发奠定科学基础。

The rise of antibiotic resistance urgently needs new antibacterial agents to treat bacterial infections. Bacterial biofilm inhibitors are considered as one of the effective strategies to overcome bacterial resistance to antibiotics. In the meantime, it has been found that iron chelators can accelerate the healing of chronic wounds caused by drug-resistant bacteria, suggesting that chelated iron can effectively combat bacterial infections. Pseudomonas aeruginosa PQS has been used as a template compound to design its analogues hydroxypyridones, it was found that these iron chelator compounds can effectively inhibit the formation of Pseudomonas aeruginosa biofilm. Since the PQS plays a key role in regulating PqsR quorum-sensing system and inducing the synthesis of siderophore pyoverdine, we proposed that development of a dual-effect molecule with both PqsR-targeting quorum-sensing regulation and iron chelation may be an effective strategy of drug design for bacterial biofilm inhibitors. To verify this hypothesis, this project intends to further design and synthesize a series of new derivatives of hydroxypyridinones, study their structure-activity relationship to find new drug hits of anti-bacterial biofilms; and study their effects on PqsR quorum-sensing signaling pathways and siderophore signaling pathways；as well as explore or validate its targets in bacterial biofilm signaling pathway by target fishing techniques. It will lay a scientific foundation for the development of new pseudomonas aeruginosa biofilm inhibitors based on dual inhibition strategy of bacterial signal pathways.