Design and Synthesis of Novel c-di-GMP G-Quadruplex Inducers as Bacterial Biofilm Inhibitors

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-diGMP-mediated biofilm regulatory pathway, was proposed in this study. In this new strategy, a series of novel c-di-GMP Gquadruplex inducers were designed and synthesized for development of therapeutic biofilm inhibitors. Compound 5h exhibited favorable c-di-GMP G-quadruplex-inducing activity and 62.18 +/- 6.76% biofilm inhibitory activity at 1.25 mu M without any DNA intercalation effect. Moreover, the favorable performance of 5h 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 5h.

Automated summary

The study proposed a new antibiofilm strategy involving the induction of dysfunctional G-quadruplexes by c-di-GMP to block the biofilm regulatory pathway. Compound 5h exhibited favorable c-di-GMP G-quadruplex-inducing and biofilm inhibitory activities, without any DNA intercalation effect. The performance of 5h in interfering with c-di-GMP-related biological functions was confirmed through reporter strain and transcriptome analysis.