When Second Messenger Signaling Meets Resistance: (p)ppGpp, C-di-GMP and C-di-AMP as Masters of Antibiotic Stress Adaptation

Antimicrobial resistance represents a critical global health challenge, necessitating deeper insights into bacterial regulatory networks that govern adaptive survival and can be exploited as novel targets for drug discovery. Among these, nucleotide-based second messengers have emerged as central modulators of bacterial physiology and stress responses. Cyclic dinucleotides, including c-di-GMP and c-di-AMP, alongside the alarmone (p)ppGpp, orchestrate diverse cellular processes required for bacterial survival, pathogenesis, and metabolic regulation. Accumulating evidence highlights their pivotal role in shaping antimicrobial susceptibility through biofilm formation, transcriptional regulation, influencing target accessibility, efflux pump expression, persistence, and tolerance phenotypes. Dysregulation of these signaling pathways could promote the evolution of resistance, either directly or indirectly, by modulating fitness landscapes and stress-induced mutagenesis. This review summarizes the current knowledge of global regulators (c-di-GMP, c-di-AMP, and (p)ppGpp) with respect to their contributions in governing AMR in priority pathogens, emphasizing their potential as promising targets for novel antimicrobial and antibiofilm strategies.