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-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 5h 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 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.