Cyclic dinucleotide signaling in mycobacteria: Roles of c-di-AMP and c-di-GMP in physiology and pathogenesis

Cyclic dinucleotides (CDNs), particularly cyclic di-AMP (c-di-AMP) and cyclic di-GMP (c-di-GMP), are now recognised as major second messengers that governs critical physiological and pathogenic processes in Mycobacterium tuberculosis. Beyond their central roles in cell wall homeostasis, DNA repair, metabolism, stress responses, and virulence, these signaling molecules also strongly influence host immunity through activation of the cGAS-STING pathway, generating significant interest in their potential as vaccine adjuvants. This review synthesizes recent progress in understanding CDN biosynthesis and degradation, the identification of new effector and receptor proteins, and the expanding regulatory networks governed by these molecules in mycobacteria. Emerging findings highlight the essential role of c-di-AMP in bacterial growth and genome integrity surveillance, the established involvement of c-di-GMP in lifestyle transitions, and the potent immunomodulatory properties of both CDNs. Targeting CDN signaling pathways or harnessing their immune-stimulatory functions, offers promising avenues for developing next-generation antimycobacterial therapeutics and improved vaccine strategies. This review integrates current advances, highlights recent breakthroughs, and outlines future challenges in decoding CDN signaling in mycobacteria.