Production of Bioactive Metabolites in Streptomyces coelicolor Cultivated in the Presence of Citrus Seeds

Plant–microbe interactions can modulate the production of bioactive compounds involved in plant growth-promoting activity. This study investigates the metabolic reprogramming of the actinomycete model strain Streptomyces coelicolor M145 during co-cultivation with Citrus aurantium and Citrus limon seeds, used as defined plant-derived chemical inputs, under contrasting nutritional conditions with or without L-tryptophan (Trp) supplementation. Untargeted metabolome profiling revealed medium- and Citrus seed-dependent metabolic shifts in co-cultures compared with corresponding Citrus seed and S. coelicolor single cultures used as controls. Under R2YE production conditions, co-cultivation with C. limon resulted in 27 extracellular metabolites, compared with 11 detected in the TSB vegetative medium; similar trends were observed for C. aurantium. Multivariate analyses confirmed that growth medium, Citrus species, and Trp significantly shaped S. coelicolor extracellular metabolic profiles, mainly in quantitative terms. Production conditions, particularly with Trp supplementation, promoted metabolites associated with antimicrobial activity and iron acquisition, whereas vegetative conditions promoted primary metabolism and biotransformation of Citrus-derived compounds. Spent medium bioassays on Solanum lycopersicum showed that these metabolic differences were correlated with distinct biological responses. Overall, these findings demonstrate that defined plant-derived inputs modulate S. coelicolor specialized metabolism in a context-dependent manner, generating metabolomic signatures associated with differential plant growth responses compared to single cultures.