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Abstract：
To address the issue of multidrug resistance in Pseudomonas aeruginosa, a novel catechol-zingerone conjugate (1) linked via a non-hydrolyzable 1,2,3-triazole linker was synthesized and subjected to biological evaluation based on the Trojan horse strategy. To enhance the efficacy, catechol, a xenosiderophore, utilized by P. aeruginosa for iron assimilation, and the dietary phytochemical zingerone, known for its anti-virulent activity against Pseudomonas aeruginosa, were exploited in the present study. Theoretical validation of conjugate (1) was conducted by in silico molecular docking analysis to determine the interaction with outer membrane transport receptor PirA and quorum sensing signal receptors. In addition, nine-fold binding affinity of Conjugate (1) toward PirA (5FP2) in comparison to its natural ligand catechol with D-score -1.13 Å authenticated the designed Trojan horse drug. Conjugate (1) showed stronger anti-virulent activity than zingerone; hence, it exhibited a promising anti-biofilm efficacy as assessed by crystal violet assay and visualized by FESEM toward P. aeruginosa. Encouraging results against P. aeruginosa in terms of quorum sensing regulated virulence factors, motility phenotypes, and biofilm formation with no cell cytotoxicity and could help open hitherto unexplored possibilities of establishing Trojan horse drugs as a successful approach against multidrug resistance in P. aeruginosa.
摘要：
为了解决铜绿假单胞菌的多药耐药问题，合成了通过不可水解的1,2,3-三唑接头连接的新型儿茶酚-姜酮缀合物(1),并基于特洛伊木马策略进行生物学评价。为了提高疗效，儿茶酚,一种异铁皮细胞，铜绿假单胞菌用于铁同化，和饮食中的植物化学物质姜根酮，以其对铜绿假单胞菌的抗毒活性而闻名，在本研究中被利用。通过计算机分子对接分析进行缀合物(1)的理论验证,以确定与外膜转运受体PirA和群体感应信号受体的相互作用。此外,缀合物（1）对PirA（5FP2）的结合亲和力是其天然配体儿茶酚的9倍，D评分为-1.13，从而验证了设计的特洛伊木马药物。缀合物(1)显示出比姜酮更强的抗毒活性；因此，通过结晶紫测定法评估并通过FESEM对铜绿假单胞菌显示出有希望的抗生物膜功效。就群体感应调节的毒力因子而言，针对铜绿假单胞菌的令人鼓舞的结果，运动性表型，和生物膜形成，没有细胞毒性，并且可以帮助打开迄今为止尚未探索的建立特洛伊木马药物的可能性，作为一种成功的方法来对抗铜绿假单胞菌的多药耐药性。
