Cyclic Di-GMP Signaling in Bacterial Biofilm Regulation

The second messenger cyclic di-guanylate monophosphate (c-di-GMP) orchestrates the transition between planktonic motility and sessile biofilm lifestyles in bacteria. Synthesised by diguanylate cyclases (DGCs) bearing GGDEF domains and degraded by specific phosphodiesterases (PDEs) carrying EAL or HD-GYP domains, c-di-GMP influences exopolysaccharide production, flagellar motility and surface adhesion. Spatiotemporal regulation arises from both global cellular pools and local signalling modules, where discrete DGC–PDE interactions and receptor clusters yield precise control. Binding of c-di-GMP to effector proteins or riboswitches triggers conformational changes that activate biofilm matrix synthesis, repress motility and modulate cell–cell and host–microbe interactions. This regulatory network underpins virulence, environmental adaptation and developmental processes across diverse bacterial taxa, bearing significant implications for controlling chronic infections and industrial biofouling.

Research from Nature Portfolio

Recent studies have demonstrated that upregulation of c-di-GMP is a key adaptive trait in host–microbe interactions. Experimental evolution of Pseudomonas strains revealed that mutations elevating c-di-GMP levels consistently enhance biofilm formation and host persistence, underscoring the messenger’s conserved role in symbiosis. In parallel, structural and mechanistic analysis of iron sensing in Pseudomonas aeruginosa uncovered an iron-binding CHASE4 domain that modulates the activity of a membrane-anchored diguanylate cyclase. Iron-bound CHASE4 inhibits its interaction with the cyclase, leading to increased c-di-GMP synthesis, reinforced biofilm development and reduced motility under iron-replete conditions, providing direct links between environmental cues and the c-di-GMP network.

Cyclic Di-GMP Signaling in Bacterial Biofilm Regulation publication trend

The graph below shows the total number of articles in cyclic di-gmp signaling in bacterial biofilm regulation across all publications each year (not limited to Nature Index journals).

Technical terms

c-di-GMP: A cyclic dinucleotide second messenger regulating bacterial motility, adhesion and biofilm formation.

Diguanylate cyclase (DGC): An enzyme containing a GGDEF domain that synthesises c-di-GMP from GTP.

Phosphodiesterase (PDE): An enzyme with EAL or HD-GYP domains that degrades c-di-GMP to linear products.

PilZ domain: A widespread protein domain that binds c-di-GMP and mediates downstream signalling.

Biofilm: A structured community of bacteria embedded in an extracellular matrix attached to surfaces.

References

1. Bacterial c-di-GMP has a key role in establishing host–microbe symbiosis. Nature Microbiology (2023).
2. A c-di-GMP signaling module controls responses to iron in Pseudomonas aeruginosa. Nature Communications (2024).
3. How c-di-GMP controls progression through the Streptomyces life cycle. Current Opinion in Microbiology (2024).
4. Functional diversity of c-di-GMP receptors in prokaryotic and eukaryotic systems. Cell Communication and Signaling (2023).
5. Biofilms and Cyclic di-GMP (c-di-GMP) Signaling: Lessons from Pseudomonas aeruginosa and Other Bacteria*. Journal of Biological Chemistry (2016).