Impact and applications of cyclic di-GMP second messenger signaling in biotechnology and medicine

Abstract 3′,3'-cyclic diguanylate (cyclic di-GMP) and alternative cyclic di- and oligonucleotides are ancient highly conserved signaling molecules of bacteria and archaea, which can be present in metazoans up to humans. Their impact in fundamental behavioral modes and physiological and metabolic processes, the modular organization of their signaling cascades and the versatility and flexibility of their components in microbes in combination with their far-reaching effects including stimulation of the innate and adaptive immune response in humans makes these molecules and the respective signaling cascades promising targets in antibiofilm therapy, modulation of multicellularity and tools for treatment strategies and biotechnological applications. This review will thus describe the current state-of-the-art of applications and use as therapeutic targets of cyclic di- and oligonucleotides and the limitations and challenges in the application of those molecules and their use as targets. Future possibilities to successfully exploit those molecules and their signaling cascades equally as potential shortcomings are discussed.