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Biotechnological platform for metagenomic prospection of bioactive secondary metabolites from extreme marine environments

Abstract

The microbial communities present in the ocean represent a large genetic reservoir that is still little explored. The marine environment has several habitats with unique and often extreme conditions, which allow the selection of microorganisms producing differentiated secondary metabolites (natural products). These are encoded by biosynthetic genes and have great potential for the discovery of new drugs. However, most bacterial species cannot be grown in the laboratory. Thus, the use of metagenomic prospecting of microbial communities represents a new biotechnological way to obtain bioactive metabolites with unique characteristics. The present project aims to prospect biosynthetic gene clusters (BGCs) producing new and bioactive secondary metabolites, based on metagenomic data derived from extreme marine environments. The genomes will be extracted and reconstructed from the metagenomic databases: "Ilha Deception" of an Antarctic Volcanic Island, and the "deep-sea whale-Atlantic" of a decomposing whale carcass at 4,000 meters deep. The search for BGCs will then be performed mainly using the antiSMASH tool. This step will predict the BGCs (set of enzymes responsible for the biosynthesis of a given secondary metabolite) and their putative products (secondary metabolites). Tools for predicting the structure and function of enzymes contained in the BGCs will be used to assist in silico validation and selection of prospected clusters. Similarly, biosynthetic products will be evaluated for their potential chemical novelty and biological activity using principal component analyzes (PCA) based on the molecular descriptors of the predicted compounds in relation to previously reported natural products (UNPD-ISDB) and approved drugs (DrugBank). BGCs, potentially producers of new bioactive metabolites, will be selected for experimental production. The clusters will be assembled using the TAR (Transformation-Associated Recombination) cloning approach from fragments amplified in the laboratory using environmental DNA, or commercially obtained synthetic DNA. Heterologous expression will be performed in hosts of the genera Bacillus, Escherichia or Streptomyces, depending on the characteristics of the selected BGC. Finally, the obtained compounds will be evaluated for their antimicrobial and anti-cancer activities, using cytotoxicity assays. Such approach of prospecting BGCs from metagenomic data represents the latest scientific advance in the search for unprecedented bioactive molecules. By joing consolidated research groups and complementary expertise, this project should contribute to the consolidation of this biotechnological platform in the country, also helping initiatives focused on the discovery of new drugs in Brazil. (AU)

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