Genome mining of Streptomyces sp. BRB081 reveals the production of the antitumor pyrrolobenzodiazepine sibiromycin

Employing a genome mining approach, this work aimed to further explore the secondary metabolism associated genes of Streptomyces sp. BRB081, a marine isolate. The genomic DNA of BRB081 was sequenced and assembled in a synteny-based pipeline for biosynthetic gene clusters (BGCs) annotation. A total of 27 BGCs were annotated, including a sibiromycin complete cluster, a bioactive compound with potent antitumor activity. The production of sibiromycin, a pyrrolobenzodiazepine, was confirmed by the analysis of obtained BRB081 extract by HPLC-MS/MS, which showed the presence of the sibiromycin ions themselves, as well as its imine and methoxylated forms. To verify the presence of this cluster in other genomes available in public databases, a genome neighborhood network (GNN) was constructed with the non-ribosomal peptide synthetase (NRPS) gene from Streptomyces sp. BRB081. Although the literature does not report the occurrence of the sibiromycin BGC in any other microorganism than Streptosporangium sibiricum, we have located this BGC in 10 other genomes besides the BRB081 isolate, all of them belonging to the Actinomycetia class. These findings strengthen the importance of uninterrupted research for new producer strains of secondary metabolites with uncommon biological activities. These results reinforced the accuracy and robustness of genomics in the screening of natural products. Furthermore, the unprecedented nature of this discovery confirms the unknown metabolic potential of the Actinobacteria phylum and the importance of continuing screening studies in this taxon.