Systematic Genome Mining of Peptide Metallophore Pathways Uncovers Novel Dibenzo-α-Pyrone Siderophores in Streptomyces sp. HB-R818.

Metallophores are metal-chelating natural products that enable microorganisms to acquire essential metal ions and mediate processes such as iron uptake, quorum sensing, and interspecies competition. Metallophores also display potent antimicrobial and anticancer activities, highlighting their biomedical and biotechnological potential. Despite Streptomyces being prolific producers of bioactive metabolites, their metallophore pathways remain largely unexplored. Here, we systematically mined 519 reference Streptomyces genomes to elucidate the distribution, diversity, and structural features of metallophores and identified a new metallophore biosynthetic gene cluster (BGC) (ser) from sponge-derived Streptomyces sp. HB-R818. Using a metabologenomics-based strategy, five new siderophore analogs serobactins A-E (1-5) and known enterobactin (6) were isolated. These compounds show potential to inhibit tumor invasion and feature a unique dibenzo-α-pyrone scaffold in structure, formed through the cyclization of an extra 2,3-dihydroxybenzoic acid with 2,3-dihydroxybenzoyl serine. The BGC (ser) was validated by the nonribosomal peptide synthetase gene knockout; the biosynthesis of 1-6 was proposed.