Cyclic Dinucleotide Signaling in Bacterial Systems

Cyclic dinucleotides are a class of nucleotide-based second messengers that orchestrate a wide array of physiological processes in bacteria. These small molecules, including cyclic di-adenosine monophosphate (c-di-AMP) and cyclic di-guanosine monophosphate (c-di-GMP), are synthesised by dedicated cyclase enzymes and degraded by specific phosphodiesterases. They exert their regulatory effects by binding to protein receptors, riboswitches and enzyme targets, thereby modulating cell wall homeostasis, osmoregulation, DNA repair, virulence factor expression and biofilm formation. The precise control of intracellular cyclic dinucleotide levels is critical to bacterial survival, as imbalances can lead to growth defects or heightened susceptibility to environmental stress. Recent advances in structural biology and genomics have deepened our understanding of how these molecules interface with transport systems, transcriptional regulators and stress-response pathways. Given their central role in bacterial physiology and pathogenicity, components of cyclic dinucleotide signalling networks have emerged as promising targets for novel antimicrobial strategies.

Research from Nature Portfolio

Recent studies have used cryo-electron microscopy combined with functional assays and molecular dynamics simulations to elucidate how c-di-AMP directly regulates a key potassium transporter in Bacillus subtilis. Structural snapshots reveal that binding of c-di-AMP to the cytosolic domain of the KimA symporter induces immobilisation of transmembrane helices, trapping the protein in an inward-occluded conformation. This regulatory mechanism prevents excessive potassium uptake under conditions of high intracellular ion concentration, thereby safeguarding osmotic balance. The integration of high-resolution structures with biochemical data provides a detailed molecular framework for understanding how cyclic dinucleotides control ion transport at the membrane interface.

Cyclic Dinucleotide Signaling in Bacterial Systems publication trend

The graph below shows the total number of articles in cyclic dinucleotide signaling in bacterial systems across all publications each year (not limited to Nature Index journals).

Technical terms

Second messenger: A small intracellular signalling molecule that transmits external or metabolic cues to effectors, thereby coordinating cellular responses.

Cyclic dinucleotide: A signalling nucleotide composed of two nucleoside monophosphates cyclised via phosphodiester bonds, acting as a regulatory ligand.

Diadenylate cyclase: An enzyme that catalyses the formation of c-di-AMP from two ATP molecules.

Phosphodiesterase: An enzyme that hydrolyses cyclic dinucleotides into linear dinucleotides or mononucleotides, thereby terminating the signal.

Riboswitch: A regulatory RNA element that binds a small metabolite or nucleotide, controlling gene expression by altering RNA structure.

References

1. Cyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation. Nature Communications (2023).
2. Cyclic-di-AMP signalling in lactic acid bacteria. FEMS Microbiology Reviews (2023).
3. The role of cyclic nucleotides in bacterial antimicrobial resistance and tolerance. Trends in Microbiology (2024).