Cyclic di‐GMP signaling—Where did you come from and where will you go?

Abstract

Microbes including bacteria are required to respond to their often continuously changing ecological niches in order to survive. While many signaling molecules are produced as seemingly circumstantial byproducts of common biochemical reactions, there are a few second messenger signaling systems such as the ubiquitous cyclic di‐GMP second messenger system that arise through the synthesis of dedicated multidomain enzymes triggered by multiple diverse external and internal signals. Being one of the most numerous and widespread signaling system in bacteria, cyclic di‐GMP signaling contributes to adjust physiological and metabolic responses in all available ecological niches. Those niches range from deep‐sea and hydrothermal springs to the intracellular environment in human immune cells such as macrophages. This outmost adaptability is possible by the modularity of the cyclic di‐GMP turnover proteins which enables coupling of enzymatic activity to the diversity of sensory domains and the flexibility in cyclic di‐GMP binding sites. Nevertheless, commonly regulated fundamental microbial behavior include biofilm formation, motility, and acute and chronic virulence. The dedicated domains carrying out the enzymatic activity indicate an early evolutionary origin and diversification of “bona fide” second messengers such as cyclic di‐GMP which is estimated to have been present in the last universal common ancestor of archaea and bacteria and maintained in the bacterial kingdom until today. This perspective article addresses aspects of our current view on the cyclic di‐GMP signaling system and points to knowledge gaps that still await answers.

Genetic disruption of the bacterial raiA motif noncoding RNA causes defects in sporulation and aggregation

“…This juxtaposition of genes involved in natural competence and translation arrest is broadly conserved, even among distantly related bacteria that lack the raiA motif RNA, and is consistent with competence as a developmental program that is often concomitant with growth arrest or a decrease in rRNA production ( 57 , 58 ). Given the importance of cyclic dinucleotide signaling to bacterial physiological changes ( 59 – 61 ), and given that these signaling molecules likely emerged during the RNA World ( 62 , 63 ), an intriguing possibility is that raiA motif RNAs serve as receptors or as ribozymes involved in cyclic dinucleotide signaling processes.…”

Gene expression reprogramming of Pseudomonas alloputida in response to arginine through the transcriptional regulator ArgR

“…The transition between planktonic and sessile existence involves changes in gene expression and metabolism of bacterial cells, associated with variations in the intracellular levels of the second messenger cyclic diguanylate (c-di-GMP) [4,5]. These, in turn, are modulated in response to chemical environmental and metabolic cues, as well as physical stimuli [6][7][8]. Among the molecules that influence c-di-GMP signalling and biofilm development, a noteworthy role has been ascribed to certain amino acids.…”

Host cell-based screening assays for identification of molecules targeting Pseudomonas aeruginosa cyclic di-GMP signaling and biofilm formation

“…Recent research efforts have focused on targeting regulatory pathways, with the intracellular second messenger c-di-GMP emerging as a promising drug target ( Caly et al, 2015 ; Andersen et al, 2021 ). C-di-GMP serves as a signaling molecule present in virtually all bacteria, regulating crucial processes including antibiotic resistance, biofilm formation, and virulence ( Römling, 2023 ).…”

“…Targeting the c-di-GMP signaling pathway in P. aeruginosa offers a promising strategy to combat antibiotic-resistant infections ( Caly et al, 2015 ; An and Ryan, 2016 ; Andersen et al, 2021 ). By manipulating c-di-GMP levels, it is possible to influence key virulence traits of the bacterium, including biofilm formation and the production of virulence factors ( Bjarnsholt et al, 2010 ; Andersen et al, 2021 ; Mamat et al, 2023 ; Römling, 2023 ). This approach provides a unique opportunity to attenuate the pathogenicity of P. aeruginosa without exerting selective pressure for the development of antibiotic resistance.…”