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

2020 ◽  
Vol 8 (4) ◽  
pp. 616 ◽  
Author(s):  
Chung Thanh Nguyen ◽  
Dipesh Dhakal ◽  
Van Thuy Thi Pham ◽  
Hue Thi Nguyen ◽  
Jae-Kyung Sohng
Keyword(s):  
Bioactive Compounds ◽  
State Of The Art ◽  
Rapid Development ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Microbial Genomes ◽  
Streptomyces Spp ◽  
Pharmaceutical Industries

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.

scholarly journals Detecting and prioritizing biosynthetic gene clusters for bioactive compounds in bacteria and fungi

2019 ◽  
Vol 103 (8) ◽  
pp. 3277-3287 ◽  
Author(s):  
Phuong Nguyen Tran ◽  
Ming-Ren Yen ◽  
Chen-Yu Chiang ◽  
Hsiao-Ching Lin ◽  
Pao-Yang Chen
Keyword(s):  
Bioactive Compounds ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Bacteria And Fungi

scholarly journals Genomic analysis of siderophore β-hydroxylases reveals divergent stereocontrol and expands the condensation domain family

2019 ◽  
Vol 116 (40) ◽  
pp. 19805-19814 ◽  
Author(s):  
Zachary L. Reitz ◽  
Clifford D. Hardy ◽  
Jaewon Suk ◽  
Jean Bouvet ◽  
Alison Butler
Keyword(s):  
Predictive Power ◽  
Genome Mining ◽  
Genomic Analysis ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Peptide Synthetase ◽  
Condensation Domain

Genome mining of biosynthetic pathways streamlines discovery of secondary metabolites but can leave ambiguities in the predicted structures, which must be rectified experimentally. Through coupling the reactivity predicted by biosynthetic gene clusters with verified structures, the origin of the β-hydroxyaspartic acid diastereomers in siderophores is reported herein. Two functional subtypes of nonheme Fe(II)/α-ketoglutarate–dependent aspartyl β-hydroxylases are identified in siderophore biosynthetic gene clusters, which differ in genomic organization—existing either as fused domains (IβHAsp) at the carboxyl terminus of a nonribosomal peptide synthetase (NRPS) or as stand-alone enzymes (TβHAsp)—and each directs opposite stereoselectivity of Asp β-hydroxylation. The predictive power of this subtype delineation is confirmed by the stereochemical characterization of β-OHAsp residues in pyoverdine GB-1, delftibactin, histicorrugatin, and cupriachelin. The l-threo (2S, 3S) β-OHAsp residues of alterobactin arise from hydroxylation by the β-hydroxylase domain integrated into NRPS AltH, while l-erythro (2S, 3R) β-OHAsp in delftibactin arises from the stand-alone β-hydroxylase DelD. Cupriachelin contains both l-threo and l-erythro β-OHAsp, consistent with the presence of both types of β-hydroxylases in the biosynthetic gene cluster. A third subtype of nonheme Fe(II)/α-ketoglutarate–dependent enzymes (IβHHis) hydroxylates histidyl residues with l-threo stereospecificity. A previously undescribed, noncanonical member of the NRPS condensation domain superfamily is identified, named the interface domain, which is proposed to position the β-hydroxylase and the NRPS-bound amino acid prior to hydroxylation. Through mapping characterized β-OHAsp diastereomers to the phylogenetic tree of siderophore β-hydroxylases, methods to predict β-OHAsp stereochemistry in silico are realized.

scholarly journals Recent advances in the genome mining of Aspergillus secondary metabolites (covering 2012–2018)

MedChemComm ◽  
2019 ◽  
Vol 10 (6) ◽  
pp. 840-866 ◽  
Author(s):  
Jillian Romsdahl ◽  
Clay C. C. Wang
Keyword(s):  
Aspergillus Terreus ◽  
Genome Mining ◽  
Gene Clusters ◽  
Genetic Identification ◽  
Biosynthetic Pathways ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
The Past ◽  
Made In

This review covers advances made in genome mining SMs produced by Aspergillus nidulans, Aspergillus fumigatus, Aspergillus niger, and Aspergillus terreus in the past six years (2012–2018). Genetic identification and molecular characterization of SM biosynthetic gene clusters, along with proposed biosynthetic pathways, is discussed in depth.

scholarly journals Activation and Identification of a Griseusin Cluster in Streptomyces sp. CA-256286 by Employing Transcriptional Regulators and Multi-Omics Methods

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6580
Author(s):  
Charlotte Beck ◽  
Tetiana Gren ◽  
Francisco Javier Ortiz-López ◽  
Tue Sparholt Jørgensen ◽  
Daniel Carretero-Molina ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Genome Mining ◽  
Gene Clusters ◽  
Transcriptional Regulators ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Heterologous Host ◽  
Streptomyces Sp ◽  
Identification And Characterization

Streptomyces are well-known producers of a range of different secondary metabolites, including antibiotics and other bioactive compounds. Recently, it has been demonstrated that “silent” biosynthetic gene clusters (BGCs) can be activated by heterologously expressing transcriptional regulators from other BGCs. Here, we have activated a silent BGC in Streptomyces sp. CA-256286 by overexpression of a set of SARP family transcriptional regulators. The structure of the produced compound was elucidated by NMR and found to be an N-acetyl cysteine adduct of the pyranonaphtoquinone polyketide 3′-O-α-d-forosaminyl-(+)-griseusin A. Employing a combination of multi-omics and metabolic engineering techniques, we identified the responsible BGC. These methods include genome mining, proteomics and transcriptomics analyses, in combination with CRISPR induced gene inactivations and expression of the BGC in a heterologous host strain. This work demonstrates an easy-to-implement workflow of how silent BGCs can be activated, followed by the identification and characterization of the produced compound, the responsible BGC, and hints of its biosynthetic pathway.

scholarly journals The antiSMASH database version 3: increased taxonomic coverage and new query features for modular enzymes

2020 ◽  
Vol 49 (D1) ◽  
pp. D639-D643 ◽  
Author(s):  
Kai Blin ◽  
Simon Shaw ◽  
Satria A Kautsar ◽  
Marnix H Medema ◽  
Tilmann Weber
Keyword(s):  
User Interface ◽  
Graphical User Interface ◽  
Genome Mining ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
High Quality ◽  
Microbial Genomes ◽  
Fungal Genomes ◽  
Interactive Graphical User Interface

Abstract Microorganisms produce natural products that are frequently used in the development of antibacterial, antiviral, and anticancer drugs, pesticides, herbicides, or fungicides. In recent years, genome mining has evolved into a prominent method to access this potential. antiSMASH is one of the most popular tools for this task. Here, we present version 3 of the antiSMASH database, providing a means to access and query precomputed antiSMASH-5.2-detected biosynthetic gene clusters from representative, publicly available, high-quality microbial genomes via an interactive graphical user interface. In version 3, the database contains 147 517 high quality BGC regions from 388 archaeal, 25 236 bacterial and 177 fungal genomes and is available at https://antismash-db.secondarymetabolites.org/.

scholarly journals IMG-ABC v.5.0: an update to the IMG/Atlas of Biosynthetic Gene Clusters Knowledgebase

2019 ◽  
Author(s):  
Krishnaveni Palaniappan ◽  
I-Min A Chen ◽  
Ken Chu ◽  
Anna Ratner ◽  
Rekha Seshadri ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolism ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Microbial Genomes ◽  
Initial Release ◽  
Systematic Identification ◽  
Biomedical Potential ◽  
Biosynthetic Machinery

Abstract Microbial secondary metabolism is a reservoir of bioactive compounds of immense biotechnological and biomedical potential. The biosynthetic machinery responsible for the production of these secondary metabolites (SMs) (also called natural products) is often encoded by collocated groups of genes called biosynthetic gene clusters (BGCs). High-throughput genome sequencing of both isolates and metagenomic samples combined with the development of specialized computational workflows is enabling systematic identification of BGCs and the discovery of novel SMs. In order to advance exploration of microbial secondary metabolism and its diversity, we developed the largest publicly available database of predicted BGCs combined with experimentally verified BGCs, the Integrated Microbial Genomes Atlas of Biosynthetic gene Clusters (IMG-ABC) (https://img.jgi.doe.gov/abc-public). Here we describe the first major content update of the IMG-ABC knowledgebase, since its initial release in 2015, refreshing the BGC prediction pipeline with the latest version of antiSMASH (v5) as well as presenting the data in the context of underlying environmental metadata sourced from GOLD (https://gold.jgi.doe.gov/). This update has greatly improved the quality and expanded the types of predicted BGCs compared to the previous version.

Phylogeny of the Bacillus altitudinis Complex and Characterization of a Newly Isolated Strain with Antilisterial Activity

2021 ◽  
Author(s):  
Lauren Kathryn Hudson ◽  
Leticia A.G. Orellana ◽  
Daniel W Bryan ◽  
Andrew Moore ◽  
John P. Munafo ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Foodborne Pathogens ◽  
Food Industry ◽  
Gene Clusters ◽  
Single Species ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Bacillus Altitudinis ◽  
Biocontrol Potential

Here, a Bacillus strain, UTK D1-0055, is described that was isolated from a laboratory environment. It was of interest as it demonstrated antilisterial activity. The genome was sequenced, which identified the strain as Bacillus altitudinis, and a high-quality complete annotated genome was produced. Additionally, the taxonomy of this and related species was evaluated, including B. aerophilus, B. pumilus, B. safensis, B. stratosphericus, and B. xiamensis, which is unclear and contains errors in public databases such as NCBI. The included strains grouped into seven clusters based on average nucleotide identity (ANI). Strains designated as B. aerophilus, B. altitudinis, and B. stratosphericus grouped together in the cluster containing the B. altitudinis type strain, suggesting that they should be considered a single species, B. altitudinis. Furthermore, the antimicrobial activity of UTK D1-0055 was determined against a panel of 15 Listeria spp. strains (including nine L. monocytogenes serotypes, L. innocua, and L. marthii), other foodborne pathogens (six Salmonella enterica serotypes and Escherichia coli), and three representative fungi (Saccharomyces cerevisiae, Botrytis cinerea, and Hyperdermium pulvinatum). Antibacterial activity was observed against all Listeria spp. strains, but no antagonistic effects were observed against the other bacterial or fungal strains tested. Biosynthetic gene clusters were identified in silico that may be related to the observed antibacterial activity, which included clusters that putatively encode bacteriocins and nonribosomally synthesized peptides. The Bacillus altitudinis strain identified in the present investigation showed a broad range of antilisterial activity, suggesting that it and other related strains may potentially be evaluated for their biocontrol potential in the food industry.

scholarly journals Large-Scale Metagenome Assembly Reveals Novel Animal-Associated Microbial Genomes, Biosynthetic Gene Clusters, and Other Genetic Diversity

mSystems ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
Nicholas D. Youngblut ◽  
Jacobo de la Cuesta-Zuluaga ◽  
Georg H. Reischer ◽  
Silke Dauser ◽  
Nathalie Schuster ◽  
...  
Keyword(s):  
Large Scale ◽  
Animal Species ◽  
Gene Clusters ◽  
Genomic Diversity ◽  
Data Sets ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Microbial Genomes ◽  
Metagenome Assembly ◽  
Gut Metagenome

ABSTRACT Large-scale metagenome assemblies of human microbiomes have produced a vast catalogue of previously unseen microbial genomes; however, comparatively few microbial genomes derive from other vertebrates. Here, we generated 5,596 metagenome-assembled genomes (MAGs) from the gut metagenomes of 180 predominantly wild animal species representing 5 classes, in addition to 14 existing animal gut metagenome data sets. The MAGs comprised 1,522 species-level genome bins (SGBs), most of which were novel at the species, genus, or family level, and the majority were enriched in host versus environment metagenomes. Many traits distinguished SGBs enriched in host or environmental biomes, including the number of antimicrobial resistance genes. We identified 1,986 diverse biosynthetic gene clusters; only 23 clustered with any MIBiG database references. Gene-based assembly revealed tremendous gene diversity, much of it host or environment specific. Our MAG and gene data sets greatly expand the microbial genome repertoire and provide a broad view of microbial adaptations to the vertebrate gut. IMPORTANCE Microbiome studies on a select few mammalian species (e.g., humans, mice, and cattle) have revealed a great deal of novel genomic diversity in the gut microbiome. However, little is known of the microbial diversity in the gut of other vertebrates. We studied the gut microbiomes of a large set of mostly wild animal species consisting of mammals, birds, reptiles, amphibians, and fish. Unfortunately, we found that existing reference databases commonly used for metagenomic analyses failed to capture the microbiome diversity among vertebrates. To increase database representation, we applied advanced metagenome assembly methods to our animal gut data and to many public gut metagenome data sets that had not been used to obtain microbial genomes. Our resulting genome and gene cluster collections comprised a great deal of novel taxonomic and genomic diversity, which we extensively characterized. Our findings substantially expand what is known of microbial genomic diversity in the vertebrate gut.

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