Discovery of microbial natural products by activation of silent biosynthetic gene clusters

2015 ◽  
Vol 13 (8) ◽  
pp. 509-523 ◽  
Author(s):  
Peter J. Rutledge ◽  
Gregory L. Challis
Keyword(s):  
Natural Products ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Microbial Natural Products

A Natural Product Chemist's Guide to Unlocking Silent Biosynthetic Gene Clusters

2021 ◽  
Vol 90 (1) ◽  
Author(s):  
Brett C. Covington ◽  
Fei Xu ◽  
Mohammad R. Seyedsayamdost
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Gene Clusters ◽  
Annual Review ◽  
Publication Date ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Research And Innovation ◽  
Therapeutic Leads ◽  
Microbial Natural Products

Microbial natural products have provided an important source of therapeutic leads and motivated research and innovation in diverse scientific disciplines. In recent years, it has become evident that bacteria harbor a large, hidden reservoir of potential natural products in the form of silent or cryptic biosynthetic gene clusters (BGCs). These can be readily identified in microbial genome sequences but do not give rise to detectable levels of a natural product. Herein, we provide a useful organizational framework for the various methods that have been implemented for interrogating silent BGCs. We divide all available approaches into four categories. The first three are endogenous strategies that utilize the native host in conjunction with classical genetics, chemical genetics, or different culture modalities. The last category comprises expression of the entire BGC in a heterologous host. For each category, we describe the rationale, recent applications, and associated advantages and limitations. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals A chromatogram-simplified Streptomyces albus host for heterologous production of natural products

2019 ◽  
Author(s):  
Asif Fazal ◽  
Divya Thankachan ◽  
Ellie Harris ◽  
Ryan F. Seipke
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Gene Clusters ◽  
Heterologous Production ◽  
Biosynthetic Gene ◽  
Critical Aspect ◽  
Biosynthetic Gene Clusters ◽  
Streptomyces Albus ◽  
Microbial Natural Products ◽  
Suitable Expression

AbstractCloning natural product biosynthetic gene clusters from cultured or uncultured sources and their subsequent expression by genetically tractable heterologous hosts is an essential strategy for the elucidation and characterisation of novel microbial natural products. The availability of suitable expression hosts is a critical aspect of this workflow. In this work, we mutagenised five endogenous biosynthetic gene clusters from Streptomyces albus S4, which reduced the complexity of chemical extracts generated from the strain and eliminated antifungal and antibacterial bioactivity. We showed that the resulting quintuple mutant can express foreign BGCs by heterologously producing actinorhodin, cinnamycin and prunustatin. We envisage that our strain will be a useful addition to the growing suite of heterologous expression hosts available for exploring microbial secondary metabolism.

scholarly journals A chromatogram-simplified Streptomyces albus host for heterologous production of natural products

2019 ◽  
Vol 113 (4) ◽  
pp. 511-520 ◽  
Author(s):  
Asif Fazal ◽  
Divya Thankachan ◽  
Ellie Harris ◽  
Ryan F. Seipke
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Gene Clusters ◽  
Heterologous Production ◽  
Biosynthetic Gene ◽  
Critical Aspect ◽  
Biosynthetic Gene Clusters ◽  
Streptomyces Albus ◽  
Microbial Natural Products ◽  
Suitable Expression

AbstractCloning natural product biosynthetic gene clusters from cultured or uncultured sources and their subsequent expression by genetically tractable heterologous hosts is an essential strategy for the elucidation and characterisation of novel microbial natural products. The availability of suitable expression hosts is a critical aspect of this workflow. In this work, we mutagenised five endogenous biosynthetic gene clusters from Streptomyces albus S4, which reduced the complexity of chemical extracts generated from the strain and eliminated antifungal and antibacterial bioactivity. We showed that the resulting quintuple mutant can express foreign biosynthetic gene clusters by heterologously producing actinorhodin, cinnamycin and prunustatin. We envisage that our strain will be a useful addition to the growing suite of heterologous expression hosts available for exploring microbial secondary metabolism.

scholarly journals Vertical Inheritance Facilitates Interspecies Diversification in Biosynthetic Gene Clusters and Specialized Metabolites

mBio ◽  
2021 ◽  
Author(s):  
Alexander B. Chase ◽  
Douglas Sweeney ◽  
Mitchell N. Muskat ◽  
Dulce G. Guillén-Matus ◽  
Paul R. Jensen
Keyword(s):  
Natural Products ◽  
Gene Clusters ◽  
Species Level ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Evolutionary Processes ◽  
Vertical Inheritance ◽  
Metabolite Production ◽  
Specialized Metabolites ◽  
Microbial Natural Products

Microbial natural products are traditionally exploited for their pharmaceutical potential, yet our understanding of the evolutionary processes driving BGC evolution and compound diversification remains poorly developed. While HGT is recognized as an integral driver of BGC distributions, we find that the effects of vertical inheritance on BGC diversification had direct implications for species-level specialized metabolite production.

scholarly journals Genetic platforms for heterologous expression of microbial natural products

2019 ◽  
Vol 36 (9) ◽  
pp. 1313-1332 ◽  
Author(s):  
Jia Jia Zhang ◽  
Xiaoyu Tang ◽  
Bradley S. Moore
Keyword(s):  
Natural Products ◽  
Heterologous Expression ◽  
Natural Product ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Genetic Technologies ◽  
Microbial Natural Products

This review covers current genetic technologies for accessing and manipulating natural product biosynthetic gene clusters through heterologous expression.

scholarly journals Nerpa: A Tool for Discovering Biosynthetic Gene Clusters of Bacterial Nonribosomal Peptides

Metabolites ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 693
Author(s):  
Olga Kunyavskaya ◽  
Azat M. Tagirdzhanov ◽  
Andrés Mauricio Caraballo-Rodríguez ◽  
Louis-Félix Nothias ◽  
Pieter C. Dorrestein ◽  
...  
Keyword(s):  
Natural Products ◽  
Anticancer Agents ◽  
Gene Clusters ◽  
Molecular Structures ◽  
Computational Method ◽  
Nonribosomal Peptides ◽  
Biosynthetic Gene ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Microbial Natural Products

Microbial natural products are a major source of bioactive compounds for drug discovery. Among these molecules, nonribosomal peptides (NRPs) represent a diverse class of natural products that include antibiotics, immunosuppressants, and anticancer agents. Recent breakthroughs in natural product discovery have revealed the chemical structure of several thousand NRPs. However, biosynthetic gene clusters (BGCs) encoding them are known only for a few hundred compounds. Here, we developed Nerpa, a computational method for the high-throughput discovery of novel BGCs responsible for producing known NRPs. After searching 13,399 representative bacterial genomes from the RefSeq repository against 8368 known NRPs, Nerpa linked 117 BGCs to their products. We further experimentally validated the predicted BGC of ngercheumicin from Photobacterium galatheae via mass spectrometry. Nerpa supports searching new genomes against thousands of known NRP structures, and novel molecular structures against tens of thousands of bacterial genomes. The availability of these tools can enhance our understanding of NRP synthesis and the function of their biosynthetic enzymes.

Expanding the Natural Products Heterologous Expression Repertoire in the Model Cyanobacterium Anabaena sp. Strain PCC 7120: Production of Pendolmycin and Teleocidin B-4

2019 ◽  
Author(s):  
Patrick Videau ◽  
Kaitlyn Wells ◽  
Arun Singh ◽  
Jessie Eiting ◽  
Philip Proteau ◽  
...  
Keyword(s):  
Natural Products ◽  
Genome Mining ◽  
Gene Clusters ◽  
Combinatorial Biosynthesis ◽  
Test Case ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Cyanobacterium Anabaena ◽  
Anabaena Sp ◽  
Pcc 7120

Cyanobacteria are prolific producers of natural products and genome mining has shown that many orphan biosynthetic gene clusters can be found in sequenced cyanobacterial genomes. New tools and methodologies are required to investigate these biosynthetic gene clusters and here we present the use of <i>Anabaena </i>sp. strain PCC 7120 as a host for combinatorial biosynthesis of natural products using the indolactam natural products (lyngbyatoxin A, pendolmycin, and teleocidin B-4) as a test case. We were able to successfully produce all three compounds using codon optimized genes from Actinobacteria. We also introduce a new plasmid backbone based on the native <i>Anabaena</i>7120 plasmid pCC7120ζ and show that production of teleocidin B-4 can be accomplished using a two-plasmid system, which can be introduced by co-conjugation.

scholarly journals Comprehensive curation and analysis of fungal biosynthetic gene clusters of published natural products

2016 ◽  
Vol 89 ◽  
pp. 18-28 ◽  
Author(s):  
Yong Fuga Li ◽  
Kathleen J.S. Tsai ◽  
Colin J.B. Harvey ◽  
James Jian Li ◽  
Beatrice E. Ary ◽  
...  
Keyword(s):  
Natural Products ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters
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