Cyclic di-AMP signaling and regulation in Staphylococcus aureus

Cyclic di-AMP (c-di-AMP) is an essential bacterial second messenger that coordinates multiple cellular processes and is closely linked to central physiology in many bacteria. In Staphylococcus aureus, both depletion and excessive accumulation of c-di-AMP impair bacterial fitness, indicating that this signaling pathway must be tightly regulated. Recent studies have identified c-di-AMP receptor proteins in S. aureus, revealing how c-di-AMP maintains osmotic balance through ion transport and influences cell envelope function and stress adaptation. These regulatory effects also influence bacterial growth and cell size, and are linked to biofilm formation and β-lactam resistance. Elevated c-di-AMP levels can alter peptidoglycan architecture and reduce autolysis, thereby increasing β-lactam resistance, whereas reduced c-di-AMP levels can increase β-lactam susceptibility. This review summarizes current understanding of c-di-AMP synthesis, degradation, and receptor-mediated signaling in S. aureus. We also discuss emerging approaches to perturbing intracellular c-di-AMP balance as potential antimicrobial strategies.