Flavobacteriaceae
spp. are key players in global biogeochemical cycling and are known for their versatile carbohydrate and peptide catabolism. However, it is currently unknown whether secondary metabolism traits underlie their broad range of occurrence across the earth’s biomes. We examined 2,680 genomes to unveil an unprecedented phylogenetic signal dictating natural product biosynthesis diversification within the
Flavobacteriaceae
family. The distribution of secondary metabolite biosynthetic gene clusters (BGCs) across genomes usually follows macroevolutionary, genus-specific patterns. Noticeably, 88.6% of the observed BGCs were inferred to lead to the biosynthesis of likely novel natural products. We found an unanticipated, large diversity of taxon-specific BGCs encoding carotenoid and flexirubin pigments, the vast majority of which awaiting formal description. In particular,
Aquimarina
and
Kordia
spp. possessed large genomes, versatile catabolic traits, and a repertoire of BGCs possibly encoding drug-inspiring polyketides, non-ribosomal peptides, or post-translationally modified peptides. Using a machine learning approach (feature selection), we reveal that marine and non-marine
Flavobacteriaceae
genomes are differentially enriched in CAZymes and peptidases with distinct functionalities and molecular targets.
IMPORTANCE
This is the most comprehensive study performed thus far on the biosynthetic potential within the
Flavobacteriaceae
family. Our findings reveal intertwined taxonomic and natural product biosynthesis diversification within the family. We posit that the carbohydrate, peptide, and secondary metabolism triad synergistically shaped the evolution of this keystone bacterial taxon, acting as major forces underpinning the broad host range and opportunistic-to-pathogenic behavior encompassed by species in the family. This study further breaks new ground for future research on select
Flavobacteriaceae
spp. as reservoirs of novel drug leads.