Recent Advances in Strategies for Activation and Discovery/Characterization of Cryptic Biosynthetic Gene Clusters in Streptomyces

Abstract

Streptomyces spp. are prolific sources of valuable natural products (NPs) that are of great interest in pharmaceutical industries such as antibiotics, anticancer chemotherapeutics, immunosuppressants, etc. Approximately two-thirds of all known antibiotics are produced by actinomycetes, most predominantly by Streptomyces. Nevertheless, in recent years, the chances of the discovery of novel and bioactive compounds from Streptomyces have significantly declined. The major hindrance for obtaining such bioactive compounds from Streptomyces is that most of the compounds are not produced in significant titers, or the biosynthetic gene clusters (BGCs) are cryptic. The rapid development of genome sequencing has provided access to a tremendous number of NP-BGCs embedded in the microbial genomes. In addition, the studies of metabolomics provide a portfolio of entire metabolites produced from the strain of interest. Therefore, through the integrated approaches of different-omics techniques, the connection between gene expression and metabolism can be established. Hence, in this review we summarized recent advancements in strategies for activating cryptic BGCs in Streptomyces by utilizing diverse state-of-the-art techniques.

Molecular mechanism of mureidomycin biosynthesis activated by introduction of an exogenous regulatory gene ssaA into Streptomyces roseosporus

“…Genome sequencing and analyses reveal that streptomycetes, as the most important sources of antibiotics for clinical use, have been greatly underestimated for the potential of new drug leads owing to the presence of a large number of unexpressed BGCs for new natural products. Therefore, establishing new methods to activate these "cryptic" BGCs have become necessary (Nguyen et al, 2020). As we know, biosynthesis of secondary metabolites in Streptomyces is regulated stringently, and the regulatory genes, especially the CSRs, often function as the "molecular switches" for gene expression in the gene clusters (Yin et al, 2019).…”

Recent Advances in the Heterologous Biosynthesis of Natural Products from Streptomyces

“…MIBiG was established in 2015 with 1170 known BGCs; up to now, MIBiG contains 1923 known secondary metabolite BGCs [48,49]. These resources provide new opportunities to discover Streptomyces natural products using the bottom-up approach [1].…”

“…Streptomyces is a group of filamentous, Gram-positive bacteria with a high GC (guanine-cytosine) content in their genomes. The secondary metabolites or natural products of Streptomyces, such as antibiotic, anticancer, antitumor, antiviral, and immune suppressive compounds, are some of the industrially important compounds that are used for biotechnological applications [1]. Streptomyces is the main source of novel secondary metabolites, including polyketides, peptides, terpenoids, alkaloids, and saccharides [2][3][4][5][6].…”

An Update on Molecular Tools for Genetic Engineering of Actinomycetes—The Source of Important Antibiotics and Other Valuable Compounds

“…Numerous strategies were developed to induce the expression of the BGCs and access the corresponding products. While general concepts and methods of natural product discovery, including new isolation and strain cultivation methods, (meta)genomics-based approaches as well as modern metabolomics-inspired technologies were highlighted in other reviews [ 43 , 45 , 46 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ], this review provides the reader with an overview on recent advances in molecular tools for the genetic engineering of actinomycetes.…”