Cyclic-di-AMP signalling in lactic acid bacteria

Abstract

Cyclic-di-AMP is a nucleotide second messenger present in Gram-positive bacteria and some Gram-negative bacteria and Archaea. The intracellular concentration of cyclic-di-AMP is adjusted in response to environmental and cellular cues, primarily through the activities of synthesis and degradation enzymes. It performs its role by binding to protein and riboswitch receptors, many of which contribute to osmoregulation. Imbalances in cyclic-di-AMP can lead to pleiotropic phenotypes, affecting aspects such as growth, biofilm formation, virulence and resistance to osmotic, acid and antibiotic stressors. This review focuses on cyclic-di-AMP signalling in lactic acid bacteria (LAB) incorporating recent experimental discoveries and presenting an analysis of signalling components from a variety of LAB including those found in food, and commensal, probiotic and pathogenic species. All LAB possess enzymes for the synthesis and degradation of cyclic-di-AMP, but they are highly variable with regards to the receptors they possess. Studies in Lactococcus and Streptococcus have revealed a conserved function for c-di-AMP in inhibiting the transport of potassium and glycine betaine, either through direct binding to transporters or to a transcriptional regulator. Structural analysis of several cyclic-di-AMP receptors from LAB has also provided insights into how this nucleotide exerts its influence.

Coordinated regulation of osmotic imbalance by c-di-AMP shapes ß-lactam tolerance in Group B Streptococcus

“…Phenotypic variability needs to be linked to the evolution of the cdA signaling network. While the regulation of osmotic homeostasis is conserved, the precise molecular mechanisms have evolved, even in closely related species (Wang et al 2022b , Schwedt et al 2023 , Turner et al 2023 , Wright and Bai 2023 ). This is probably the consequence of an ancient and essential regulatory mechanism that has had time to adapt to the specific environment and physiology of each species.…”

“…The advantage against the lytic activity of ß-lactams comes at a cost of a decreased ability to adapt to hyperosmotic environment. It is likely that the individual contribution of the transporters varies from one species to another (Wang et al 2022b , Turner et al 2023 ), depending on their physiological and environmental lifestyle, but that their simultaneous inhibition conservatively regulates ß-lactam tolerance or resistance.…”

Coordinated regulation of osmotic imbalance by c-di-AMP shapes ß-lactam tolerance in Group BStreptococcus

“…The main cellular function of cdA is to regulate turgor pressure 17 . Remarkably, the function of cdA in osmotic homeostasis is conserved in Firmicutes, but the precise molecular mechanisms have evolved, even in closely related species 18,19 . This is probably the consequence of an ancient and essential regulatory mechanism that has had time to adapt to the specific environment and physiology of each species.…”