Small nucleotide molecule-mediated interactions between bacteriophages and their hosts: mechanisms and implications

The perpetual molecular arms race between bacteriophages and their prokaryotic hosts revolves around nucleotide-derived signaling molecules that serve as pivotal regulators of offensive and defensive strategies. This review integrates contemporary advances elucidating how cyclic nucleotide monophosphates (cNMPs), bacterial second messengers (c-di-GMP, c-di-AMP, (p)ppGpp), and nucleotide-activated antiviral defense systems (CBASS, Thoeris, Pycsar, Kongming) coordinate phage-bacteria interactions through sophisticated molecular surveillance networks. We systematically analyze phage counteradaptation mechanisms that hijack nucleotide-mediated signaling pathways for replicative advantage and immune suppression, contrasted with bacterial counterstrategies employing nucleotide dynamics in restriction mechanisms and abortive infection systems. The review further examines cutting-edge biotechnological applications capitalizing on these molecular interactions, including precision phage therapeutics, engineered phage platforms, functional phage biodesign, and phage-mediated microbiome modulation. By synthesizing structural insights into nucleotide-based defense architectures with emerging phage resistance paradigms, we identify critical knowledge gaps regarding signal transduction specificity, evolutionary trade-offs in defense systems, and spatiotemporal regulation of nucleotide networks during lytic/lysogenic cycles. This comprehensive analysis provides a conceptual framework for advancing phage engineering and antimicrobial development in the post-antibiotic era.