Complex multicellularity is linked with expanded specialized metabolite production in microorganisms.

Single-celled microorganisms evolving to form cooperative multicellular units represent a key innovation in the history of life. Multicellularity enables cellular differentiation and, as such, is critical to the emergence of biological complexity. Here we investigate the hypothesis that multicellularity facilitated massive expansions in specialized metabolite production, including polyketides, non-ribosomal peptides and terpenes, across bacteria and fungi. Systematic investigations reveal that unicellular taxa are largely limited in biosynthetic potential for secondary metabolite production. By contrast, profound biosynthetic expansions in Actinomycetota, Cyanobacteriota, Myxococcota, Pezizomycotina and Agaricomycetes coincide with independent origins of multicellular development, such as the formation of mycelia and fruiting bodies. These multicellular lineages are concomitantly enriched in carbohydrate-active enzymes, suggesting that ancient chemical innovations were further shaped by catabolic processes. By linking intraspecific cooperation to the evolution of specialized metabolism, this study advances our understanding of major evolutionary transitions and provides a framework for discovering chemical compounds to counter antimicrobial resistance.