Genome-wide analysis of biosynthetic gene clusters reveals hidden metabolic diversity in bacterial fish pathogens.

Fish-pathogenic bacteria threaten global aquaculture, yet their biosynthetic capacity for secondary metabolites remains unexplored at the genomic scale. We present the first cross-genus atlas of biosynthetic gene clusters (BGCs) in prokaryotic fish pathogens, analyzing 1,855 genomes across 12 families and 14 genera. Using antiSMASH and BiG-SCAPE, we identified 13,626 BGCs encoding NRPS, PKS, RiPPs, terpenes, and siderophores, organized into 2,842 gene cluster families. Strikingly, 1,724 families (61%) lack close MIBiG reference homologs (designated here as MIBiG-distant clusters), representing potentially underexplored enzymatic diversity. Genus-level analyses revealed pronounced specialization: Pseudomonas, Mycobacterium, and Nocardia harbor NRPS/PKS-rich repertoires (> 5 BGCs/genome), while Streptococcus and Enterococcus exhibit streamlined RiPP-dominated profiles. Network analysis identified cross-taxon BGC sharing patterns consistent with horizontal gene transfer among aquatic lineages and massive within-genus expansions, with Flavobacterium RiPP families averaging 69 members. Genome-wide correlations linked GC content to BGC density (r = 0.41, p < 0.001), with genus-specific relationships ranging from r = 0.77 (Chryseobacterium) to r = -0.84 (Lactococcus), revealing compositional constraints on metabolic evolution. BGC distribution patterns reflected ecological lifestyle and suggested potential roles in iron acquisition, interspecies competition, and host colonization. This molecular inventory establishes fish-pathogenic bacteria as a strategic frontier for natural product discovery, providing a phylogenetically resolved roadmap for isolating antimicrobials, siderophores, and biofilm modulators with applications in sustainable aquaculture disease management.