Streptomyces-Fungus Co-Culture Enhances the Production of Borrelidin and Analogs: A Genomic and Metabolomic Approach

The marine Streptomyces harbor numerous biosynthetic gene clusters (BGCs) with exploitable potential. However, many secondary metabolites cannot be produced under laboratory conditions. Co-culture strategies of marine microorganisms have yielded novel natural products with diverse biological activities. In this study, we explored the metabolic profiles of co-cultures involving <i>Streptomyces</i> sp. 2-85 and <i>Cladosporium</i> sp. 3-22—derived from marine sponges. Combining Global Natural Products Social (GNPS) Molecular Networking analysis with natural product database mining, 35 potential antimicrobial metabolites annotated were detected, 19 of which were exclusive to the co-culture, with a significant increase in production. Notably, the Streptomyces-Fungus interaction led to the increased production of borrelidin and the discovery of several analogs via molecular networking. In this study, borrelidin was first applied to combat <i>Saprolegnia parasitica</i>, which caused saprolegniosis in aquaculture. We noted its superior inhibitory effects on mycelial growth with an EC₅₀ of 0.004 mg/mL and on spore germination with an EC₅₀ of 0.005 mg/mL compared to the commercial fungicide, preliminarily identifying threonyl-tRNA synthetase as its target. Further analysis of the associated gene clusters revealed an incomplete synthesis pathway with missing malonyl-CoA units for condensation within this strain, hinting at the presence of potential compensatory pathways. In conclusion, our findings shed light on the metabolic changes of marine Streptomyces and fungi in co-culture, propose the potential of borrelidin in the control of aquatic diseases, and present new prospects for antifungal applications.