College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China.
J Med Chem. 2021 Aug 12;64(15):11074-11089. doi: 10.1021/acs.jmedchem.1c00465. Epub 2021 Jul 29.
The formation of biofilms by clinical pathogens typically leads to chronic and recurring antibiotic-resistant infections. High cellular levels of cyclic diguanylate (c-di-GMP), a ubiquitous secondary messenger of bacteria, have been proven to be associated with a sessile biofilm lifestyle of pathogens. A promising antibiofilm strategy involving the induction of c-di-GMP to form dysfunctional G-quadruplexes, thereby blocking the c-di-GMP-mediated biofilm regulatory pathway, was proposed in this study. In this new strategy, a series of novel c-di-GMP G-quadruplex inducers were designed and synthesized for development of therapeutic biofilm inhibitors. Compound exhibited favorable c-di-GMP G-quadruplex-inducing activity and 62.18 ± 6.76% biofilm inhibitory activity at 1.25 μM without any DNA intercalation effect. Moreover, the favorable performance of in interfering with c-di-GMP-related biological functions, including bacterial motility and bacterial extracellular polysaccharide secretion, combined with the reporter strain and transcriptome analysis results confirmed the c-di-GMP signaling-related action mechanism of .
临床病原体形成生物膜通常会导致慢性和反复出现的抗生素耐药感染。已经证明，细菌普遍存在的第二信使环二鸟苷酸（c-di-GMP）的细胞内水平与病原体的静止生物膜生活方式有关。本研究提出了一种有前途的抗生物膜策略，涉及诱导 c-di-GMP 形成功能失调的 G-四链体，从而阻断 c-di-GMP 介导的生物膜调节途径。在这种新策略中，设计并合成了一系列新型 c-di-GMP G-四链体诱导剂，用于开发治疗性生物膜抑制剂。化合物在 1.25 μM 时表现出良好的 c-di-GMP G-四链体诱导活性和 62.18 ± 6.76%的生物膜抑制活性，而没有任何 DNA 嵌入效应。此外，化合物在干扰与 c-di-GMP 相关的生物学功能方面的良好表现，包括细菌运动性和细菌胞外多糖分泌，结合报告菌株和转录组分析结果，证实了化合物的 c-di-GMP 信号相关作用机制。
