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Case Reports
. 2022 Oct;12(10):249.
doi: 10.1007/s13205-022-03305-0. Epub 2022 Aug 27.

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

Vida M B Leite  1 , Leandro M Garrido  1 , Marcelo M P Tangerina  2 , Leticia V Costa-Lotufo  3 , Marcelo J P Ferreira  2 , Gabriel Padilla  1
Affiliations
Case Reports

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

Vida M B Leite et al. 3 Biotech. 2022 Oct.

Abstract

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.

Supplementary information: The online version contains supplementary material available at 10.1007/s13205-022-03305-0.

Keywords: Actinobacteria; Genome mining; Genomics; Secondary metabolism; Sibiromycin; Streptomyces.

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Conflict of interest statement

Conflict of interestThe authors declare that they have no conflict of interest in the publication. This research does not involve human/ animal participants.

Figures

Fig. 1
Fig. 1
Phenetic tree of BRB081. The accession number of the compared sequences is given in parentheses after the strain identification. The taxa were compared using MLSA. Results were inferred by the Maximum Likelihood method and Jukes–Cantor model (Jukes and Cantor 1969), with 1000 bootstrap replications
Fig. 2
Fig. 2
Chemical structure of sibiromycin consisting of a pyrrolo benzodiazepine ring containing a sibirosamine moiety (Almeida et al. ; Blin et al. 2019)
Fig. 3
Fig. 3
Comparison between A putative sibiromycin BGC from Streptomyces sp. BRB081 and B Streptosporangium sibiricum sibiromycin BGC (Li et al. 2009). The limits of A were defined based on homology. Correlated ORFs between A and B are represented by the same color. Dotted lines connect related and ordered ORFs in the same sequence
Fig. 4
Fig. 4
Fragmentation spectra of sibiromycin and its analogs produced by Streptomyces sp. BRB081. In each spectrum, structures are represented showing the fragmentation of the detected compounds. Blue diamonds in each spectrum represent the precursor ion selected for fragmentation
See this image and copyright information in PMC

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