Pyridine Nucleotides as Emerging Targets and Agents in Antimicrobial Drug Discovery: A Comprehensive Review

The growing threat of antimicrobial resistance (AMR) necessitates the exploration of novel therapeutic targets distinct from those addressed by conventional antibiotics. Pyridine nucleotides, including NAD⁺ , NADH, NADP⁺ , and NADPH, are indispensable coenzymes involved in redox balance, energy metabolism, and biosynthetic processes in microbes. Their centrality to microbial physiology and divergence from human metabolic pathways make them attractive candidates for antimicrobial intervention. This review provides a comprehensive analysis of the chemistry and biosynthesis of pyridine nucleotides, the microbial enzymes that depend on them, and their potential as targets for drug discovery. We discuss structural modification strategies leading to pyridine nucleotide analogues and derivatives with potent antimicrobial properties, highlighting their efficacy against bacteria, fungi, and protozoa. Recent advancements in high-throughput screening, structure-based drug design, and CRISPR-based validation techniques have accelerated the discovery of inhibitors targeting NAD⁺ biosynthesis and utilization. Case studies underscore the clinical potential of these approaches, with promising candidates in preclinical stages. Despite significant promise, challenges such as drug delivery, resistance, and selectivity must be addressed. Future research integrating multi-omics and combination therapy strategies could pave the way for next-generation antimicrobials targeting pyridine nucleotide metabolism.