A comparative framework of natural nisin variants: linking genetic basis to future bioengineering applications

Nisin is a commercially successful antimicrobial peptide (AMP) widely used as a food preservative. As a ribosomally synthesized and post-translationally modified peptide (RiPP), nisin belongs to a diverse family of natural variants. However, despite its importance, a systematic and comprehensive comparison of the biosynthetic gene clusters and resulting structural diversity across the entire nisin family has been a critical gap in the literature. This review provides the first comprehensive, side-by-side analysis of nisin A and all its known natural variants. We systematically compare their biosynthetic gene clusters (BGCs), post-translational modification pathways, and final amino acid sequences. This comparative analysis reveals direct correlations between the genetic architecture of each variant and its resulting structural and functional properties. By collating and organizing this information, this work establishes a critical resource that clarifies the molecular basis for the functional diversity observed in the nisin family. This study provides a foundational framework for understanding the natural diversity of nisin. The established links between genotype and phenotype serve as a rational guide for future bioengineering efforts aimed at developing novel nisin derivatives with improved stability, solubility, or specific antimicrobial activity. In the face of growing antibiotic resistance, harnessing this natural diversity holds significant potential for creating new therapeutic agents that extend beyond nisin’s traditional role in food preservation.