Metabolomic study of marine Streptomyces sp.: Secondary metabolites and the production of potential anticancer compounds

PLoS One. 2020 Dec 21;15(12):e0244385. doi: 10.1371/journal.pone.0244385. eCollection 2020.

Abstract

Resorting to a One Strain Many Compounds (OSMAC) approach, the marine Streptomyces sp. BRB081 strain was grown in six different media settings over 1, 2, 3 or 7 days. Extractions of mycelium and broth were conducted separately for each media and cultivation period by sonication using methanol/acetone 1:1 and agitation with ethyl acetate, respectively. All methanol/acetone and ethyl acetate crude extracts were analysed by HPLC-MS/MS and data treatment was performed through GNPS platform using MZmine 2 software. In parallel, the genome was sequenced, assembled and mined to search for biosynthetic gene clusters (BGC) of secondary metabolites using the AntiSMASH 5.0 software. Spectral library search tool allowed the annotation of desferrioxamines, fatty acid amides, diketopiperazines, xanthurenic acid and, remarkably, the cyclic octapeptides surugamides. Molecular network analysis allowed the observation of the surugamides cluster, where surugamide A and the protonated molecule corresponding to the B-E isomers, as well as two potentially new analogues, were detected. Data treatment through MZmine 2 software allowed to distinguish that the largest amount of surugamides was obtained by cultivating BRB081 in SCB medium during 7 days and extraction of culture broth. Using the same data treatment, a chemical barcode was created for easy visualization and comparison of the metabolites produced overtime in all media. By genome mining of BRB081 four regions of biosynthetic gene clusters of secondary metabolites were detected supporting the metabolic data. Cytotoxic evaluation of all crude extracts using MTT assay revealed the highest bioactivity was also observed for extracts obtained in the optimal conditions as those for surugamides production, suggesting these to be the main active compounds herein. This method allowed the identification of compounds in the crude extracts and guided the selection of best conditions for production of bioactive compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / isolation & purification*
  • Bacterial Proteins / genetics
  • Bacteriological Techniques
  • Biosynthetic Pathways
  • Marine Biology
  • Metabolomics / methods*
  • Multigene Family
  • Phylogeny
  • Secondary Metabolism*
  • Streptomyces / chemistry
  • Streptomyces / classification
  • Streptomyces / growth & development*
  • Whole Genome Sequencing

Substances

  • Antineoplastic Agents
  • Bacterial Proteins

Grants and funding

This research was supported by São Paulo Research Foundation (FAPESP) [grants 2017/16606-6 (M.M.P.T.), 2017/18235-5 (L.C.F.), 2017/17648-4 (A.B.) and 2015/17177-6 (L.V.C.L.)] and the Coordination for the Improvement of Higher Education Personnel - CAPES [Finance Code 001, Brazil]. L.V.C.L., M.J.P.F and N.P.L. were funded by a fellowship from the Brazilian National Council for Scientific and Technological Development - CNPq. This study is registered with the Sistema Nacional de Gestão do Patrimônio Genético e do Conhecimento Tradicional Associado [SisGen # A0031D5] within the Brazilian Environmental Ministry, and has been authorized by Instituto Florestal, within the São Paulo State Environmental Secretary [process # 260108 – 004.258/2018]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.