Zhang Yan, Jiao Fangfang, Zeng Derong, Yu Xiang, Zhou Yongqiang, Xue Juan, Yang Wude, Guo Jingjing
College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China.
Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, China.
Molecules. 2024 Nov 30;29(23):5679. doi: 10.3390/molecules29235679.
Urinary tract infections (UTIs), primarily caused by uropathogenic (UPEC), have high morbidity and recurrence rates. Resistance to levofloxacin hydrochloride (LEV), a commonly used treatment for UTIs, is increasingly problematic, exacerbated by biofilm formation mediated by interactions between cyclic di-GMP (c-di-GMP or CDG) and YcgR. In this study, we identified three caffeoylquinic acid compounds from -chlorogenic acid (CGA), sibiricose A5 (Si-A5), and 3--caffeoylquinic acid methyl ester (CAM)-that target YcgR through molecular docking. Biological assays revealed that combining these compounds with levofloxacin hydrochloride significantly enhanced antibacterial activity against standard UPEC strains in a concentration-dependent manner and clinically isolated UPEC strains. Notably, chlorogenic acid and sibiricose A5, when used with levofloxacin hydrochloride, enhanced intracellular c-di-GMP levels and swimming motility, significantly reduced YcgR gene expression, and effectively inhibited biofilm formation of UPEC at multiple time points. Additionally, molecular dynamics simulations elucidated the strong binding of these compounds to YcgR, underscoring the critical roles of residues, such as Arg118 and Asp145. This research serves as a foundation for tackling antibiotic resistance and developing innovative therapeutics for UTIs.
尿路感染（UTIs）主要由尿路致病性大肠杆菌（UPEC）引起，发病率和复发率都很高。对盐酸左氧氟沙星（LEV）这种常用的UTIs治疗药物产生耐药性的问题日益严重，由环二鸟苷酸（c-di-GMP或CDG）与YcgR之间相互作用介导的生物膜形成加剧了这一问题。在本研究中，我们从绿原酸（CGA）、西伯利亚蓼庚酮糖A5（Si-A5）和3-O-咖啡酰奎尼酸甲酯（CAM）中鉴定出三种咖啡酰奎尼酸化合物，它们通过分子对接靶向YcgR。生物学试验表明，将这些化合物与盐酸左氧氟沙星联合使用，以浓度依赖的方式显著增强了对标准UPEC菌株和临床分离的UPEC菌株的抗菌活性。值得注意的是，绿原酸和西伯利亚蓼庚酮糖A5与盐酸左氧氟沙星一起使用时，提高了细胞内c-di-GMP水平和游动性，显著降低了YcgR基因表达，并在多个时间点有效抑制了UPEC的生物膜形成。此外，分子动力学模拟阐明了这些化合物与YcgR的强结合，强调了Arg118和Asp145等残基的关键作用。本研究为解决抗生素耐药性和开发UTIs的创新治疗方法奠定了基础。
