The Experts below are selected from a list of 8898 Experts worldwide ranked by ideXlab platform
Paul R. Jensen - One of the best experts on this subject based on the ideXlab platform.
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comparative transcriptomics as a guide to Natural Product Discovery and biosynthetic gene cluster functionality
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Gregory C A Amos, Bradley S. Moore, William Fenical, Robert N Tuttle, Takayoshi Awakawa, Anne Catrin Letzel, Mincheol Kim, Yuta Kudo, Paul R. JensenAbstract:Bacterial Natural Products remain an important source of new medicines. DNA sequencing has revealed that a majority of Natural Product biosynthetic gene clusters (BGCs) maintained in bacterial genomes have yet to be linked to the small molecules whose biosynthesis they encode. Efforts to discover the Products of these orphan BGCs are driving the development of genome mining techniques based on the premise that many are transcriptionally silent during normal laboratory cultivation. Here, we employ comparative transcriptomics to assess BGC expression among four closely related strains of marine bacteria belonging to the genus Salinispora The results reveal that slightly more than half of the BGCs are expressed at levels that should facilitate Product detection. By comparing the expression profiles of similar gene clusters in different strains, we identified regulatory genes whose inactivation appears linked to cluster silencing. The significance of these subtle differences between expressed and silent BGCs could not have been predicted a priori and was only revealed by comparative transcriptomics. Evidence for the conservation of silent clusters among a larger number of strains for which genome sequences are available suggests they may be under different regulatory control from the expressed forms or that silencing may represent an underappreciated mechanism of gene cluster evolution. Coupling gene expression and metabolomics data established a bioinformatic link between the salinipostins and their associated BGC, while genetic manipulation established the genetic basis for this series of compounds, which were previously unknown from Salinispora pacifica.
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omics based Natural Product Discovery and the lexicon of genome mining
Current Opinion in Microbiology, 2017Co-Authors: Henrique Machado, Robert N Tuttle, Paul R. JensenAbstract:Genome sequencing and the application of omic techniques are driving many important advances in the field of microbial Natural Products research. Despite these gains, there remain aspects of the Natural Product Discovery pipeline where our knowledge remains poor. These include the extent to which biosynthetic gene clusters are transcriptionally active in native microbes, the temporal dynamics of transcription, translation, and Natural Product assembly, as well as the relationships between small molecule Production and detection. Here we touch on a number of these concepts in the context of continuing efforts to unlock the Natural Product potential revealed in genome sequence data and discuss nomenclatural issues that warrant consideration as the field moves forward.
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Natural Products and the gene cluster revolution
Trends in Microbiology, 2016Co-Authors: Paul R. JensenAbstract:Genome sequencing has created unprecedented opportunities for Natural-Product Discovery and new insight into the diversity and distributions of Natural-Product biosynthetic gene clusters (BGCs). These gene collectives are highly evolved for horizontal exchange, thus providing immediate opportunities to test the effects of small molecules on fitness. The marine actinomycete genus Salinispora maintains extraordinary levels of BGC diversity and has become a useful model for studies of secondary metabolism. Most Salinispora BGCs are observed infrequently, resulting in high population-level diversity while conforming to constraints associated with maximum genome size. Comparative genomics is providing a mechanism to assess secondary metabolism in the context of evolution and evidence that some Products represent ecotype-defining traits while others appear selectively neutral.
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Challenges and triumphs to genomics-based Natural Product Discovery
Journal of Industrial Microbiology & Biotechnology, 2014Co-Authors: Paul R. Jensen, Bradley S. Moore, William Fenical, Krystle L. Chavarria, Nadine ZiemertAbstract:Genome sequencing is rapidly changing the field of Natural Products research by providing opportunities to assess the biosynthetic potential of strains prior to chemical analysis or biological testing. Ready access to sequence data is driving the development of new bioinformatic tools and methods to identify the Products of silent or cryptic pathways. While genome mining has fast become a useful approach to Natural Product Discovery, it has also become clear that identifying pathways of interest is much easier than finding the associated Products. This has led to bottlenecks in the Discovery process that must be overcome for the potential of genomics-based Natural Product Discovery to be fully realized. In this perspective, we address some of these challenges in the context of our work with the marine actinomycete genus Salinispora , which is proving to be a useful model with which to apply genome mining as an approach to Natural Product Discovery.
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Discovery and assembly line biosynthesis of the lymphostin pyrroloquinoline alkaloid family of mtor inhibitors in salinispora bacteria
Journal of the American Chemical Society, 2011Co-Authors: Akimasa Miyanaga, Paul R. Jensen, Jeffrey E Janso, Leonard A Mcdonald, Hongbo Liu, Laurel R Barbieri, Alessandra S Eustaquio, Elisha N Fielding, Guy T Carter, Xidong FengAbstract:The pyrroloquinoline alkaloid family of Natural Products, which includes the immunosuppressant lymphostin, has long been postulated to arise from tryptophan. We now report the molecular basis of lymphostin biosynthesis in three marine Salinispora species that maintain conserved biosynthetic gene clusters harboring a hybrid nonribosomal peptide synthetase–polyketide synthase that is central to lymphostin assembly. Through a series of experiments involving gene mutations, stable isotope profiling, and Natural Product Discovery, we report the assembly-line biosynthesis of lymphostin and nine new analogues that exhibit potent mTOR inhibitory activity.
Ben Shen - One of the best experts on this subject based on the ideXlab platform.
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targeting bacterial genomes for Natural Product Discovery
Trends in Pharmacological Sciences, 2020Co-Authors: Edward Kalkreuter, Guohui Pan, Alexis J Cepeda, Ben ShenAbstract:Bacterial Natural Products (NPs) and their analogs constitute more than half of the new small molecule drugs developed over the past few decades. Despite this success, interest in Natural Products from major pharmaceutical companies has decreased even as genomics has uncovered the large number of biosynthetic gene clusters (BGCs) that encode for novel Natural Products. To date, there is still a lack of universal strategies and enabling technologies to discover Natural Products at scale and speed. This review highlights several of the opportunities provided by genome sequencing and bioinformatics, challenges associated with translating genomes into Natural Products, and examples of successful strain prioritization and BGC activation strategies that have been used in the genomic era for Natural Product Discovery from cultivatable bacteria.
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Strain Prioritization for Natural Product Discovery by a High- Throughput Real-Time PCR Method
2016Co-Authors: Yanwen Duan, Ben ShenAbstract:ABSTRACT: Natural Products offer unmatched chemical and structural diversity compared to other small-molecule libraries, but traditional Natural Product Discovery programs are not sustainable, demanding too much time, effort, and resources. Here we report a strain prioritization method for Natural Product Discovery. Central to the method is the application of real-time PCR, targeting genes characteristic to the bio-synthetic machinery of Natural Products with distinct scaffolds in a high-throughput format. The practicality and effectiveness of the method were showcased by prioritizing 1911 actino-mycete strains for diterpenoid Discovery. A total of 488 potential diterpenoid producers were identified, among which six were confirmed as platensimycin and platencin dual producers and one as a viguiepinol and oxaloterpin producer. While the method as described is most appropriate to prioritize strains for discovering specific Natural Products, variations of this method should be applicable to the Discovery of other classes of Natural Products. Applications of genome sequencing and genome mining to the high-priority strains could essentially eliminate the chance elements from traditional Discovery programs and fundamentall
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strain prioritization for Natural Product Discovery by a high throughput real time pcr method
Journal of Natural Products, 2014Co-Authors: Tingting Huang, Dong Yang, Jeffrey D Rudolf, Qihui Teng, Jeremy R Lohman, Yong Huang, Lixing Zhao, Yi Jiang, Yanwen Duan, Ben ShenAbstract:Natural Products offer unmatched chemical and structural diversity compared to other small-molecule libraries, but traditional Natural Product Discovery programs are not sustainable, demanding too much time, effort, and resources. Here we report a strain prioritization method for Natural Product Discovery. Central to the method is the application of real-time PCR, targeting genes characteristic to the biosynthetic machinery of Natural Products with distinct scaffolds in a high-throughput format. The practicality and effectiveness of the method were showcased by prioritizing 1911 actinomycete strains for diterpenoid Discovery. A total of 488 potential diterpenoid producers were identified, among which six were confirmed as platensimycin and platencin dual producers and one as a viguiepinol and oxaloterpin producer. While the method as described is most appropriate to prioritize strains for discovering specific Natural Products, variations of this method should be applicable to the Discovery of other classe...
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microbial genomics for the improvement of Natural Product Discovery
Current Opinion in Microbiology, 2006Co-Authors: Steven G Van Lanen, Ben ShenAbstract:The quest for the Discovery of novel Natural Products has entered a new chapter with the enormous wealth of genetic data that is now available. This information has been exploited by using whole-genome sequence mining to uncover cryptic pathways, or biosynthetic pathways for previously undetected metabolites. Alternatively, using known paradigms for secondary metabolite biosynthesis, genetic information has been 'fished out' of DNA libraries resulting in the Discovery of new Natural Products and isolation of gene clusters for known metabolites. Novel Natural Products have been discovered by expressing genetic data from uncultured organisms or difficult-to-manipulate strains in heterologous hosts. Furthermore, improvements in heterologous expression have not only helped to identify gene clusters but have also made it easier to manipulate these genes in order to generate new compounds. Finally, and perhaps the most crucial aspect of the efficient and prosperous use of the abundance of genetic information, novel enzyme chemistry continues to be discovered, which has aided our understanding of how Natural Products are biosynthesized de novo, and enabled us to rework the current paradigms for Natural Product biosynthesis.
William Fenical - One of the best experts on this subject based on the ideXlab platform.
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comparative transcriptomics as a guide to Natural Product Discovery and biosynthetic gene cluster functionality
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Gregory C A Amos, Bradley S. Moore, William Fenical, Robert N Tuttle, Takayoshi Awakawa, Anne Catrin Letzel, Mincheol Kim, Yuta Kudo, Paul R. JensenAbstract:Bacterial Natural Products remain an important source of new medicines. DNA sequencing has revealed that a majority of Natural Product biosynthetic gene clusters (BGCs) maintained in bacterial genomes have yet to be linked to the small molecules whose biosynthesis they encode. Efforts to discover the Products of these orphan BGCs are driving the development of genome mining techniques based on the premise that many are transcriptionally silent during normal laboratory cultivation. Here, we employ comparative transcriptomics to assess BGC expression among four closely related strains of marine bacteria belonging to the genus Salinispora The results reveal that slightly more than half of the BGCs are expressed at levels that should facilitate Product detection. By comparing the expression profiles of similar gene clusters in different strains, we identified regulatory genes whose inactivation appears linked to cluster silencing. The significance of these subtle differences between expressed and silent BGCs could not have been predicted a priori and was only revealed by comparative transcriptomics. Evidence for the conservation of silent clusters among a larger number of strains for which genome sequences are available suggests they may be under different regulatory control from the expressed forms or that silencing may represent an underappreciated mechanism of gene cluster evolution. Coupling gene expression and metabolomics data established a bioinformatic link between the salinipostins and their associated BGC, while genetic manipulation established the genetic basis for this series of compounds, which were previously unknown from Salinispora pacifica.
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Challenges and triumphs to genomics-based Natural Product Discovery
Journal of Industrial Microbiology & Biotechnology, 2014Co-Authors: Paul R. Jensen, Bradley S. Moore, William Fenical, Krystle L. Chavarria, Nadine ZiemertAbstract:Genome sequencing is rapidly changing the field of Natural Products research by providing opportunities to assess the biosynthetic potential of strains prior to chemical analysis or biological testing. Ready access to sequence data is driving the development of new bioinformatic tools and methods to identify the Products of silent or cryptic pathways. While genome mining has fast become a useful approach to Natural Product Discovery, it has also become clear that identifying pathways of interest is much easier than finding the associated Products. This has led to bottlenecks in the Discovery process that must be overcome for the potential of genomics-based Natural Product Discovery to be fully realized. In this perspective, we address some of these challenges in the context of our work with the marine actinomycete genus Salinispora , which is proving to be a useful model with which to apply genome mining as an approach to Natural Product Discovery.
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hybrid isoprenoid secondary metabolite Production in terrestrial and marine actinomycetes
Current Opinion in Biotechnology, 2010Co-Authors: Kelley A Gallagher, William Fenical, Paul R. JensenAbstract:Terpenoids are among the most ubiquitous and diverse secondary metabolites observed in nature. Although actinomycete bacteria are one of the primary sources of microbially derived secondary metabolites, they rarely produce compounds in this biosynthetic class. The terpenoid secondary metabolites that have been discovered from actinomycetes are often in the form of biosynthetic hybrids called hybrid isoprenoids (HIs). HIs include significant structural diversity and biological activity and thus are important targets for Natural Product Discovery. Recent screening of marine actinomycetes has led to the Discovery of a new lineage that is enriched in the Production of biologically active HI secondary metabolites. These strains represent a promising resource for Natural Product Discovery and provide unique opportunities to study the evolutionary history and ecological functions of an unusual group of secondary metabolites.
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species specific secondary metabolite Production in marine actinomycetes of the genus salinispora
Applied and Environmental Microbiology, 2007Co-Authors: Paul R. Jensen, Philip G. Williams, Lisa Zeigler, William FenicalAbstract:Here we report associations between secondary metabolite Production and phylogenetically distinct but closely related marine actinomycete species belonging to the genus Salinispora. The pattern emerged in a study that included global collection sites, and it indicates that secondary metabolite Production can be a species-specific, phenotypic trait associated with broadly distributed bacterial populations. Associations between actinomycete phylotype and chemotype revealed an effective, diversity-based approach to Natural Product Discovery that contradicts the conventional wisdom that secondary metabolite Production is strain specific. The structural diversity of the metabolites observed, coupled with gene probing and phylogenetic analyses, implicates lateral gene transfer as a source of the biosynthetic genes responsible for compound Production. These results conform to a model of selection-driven pathway fixation occurring subsequent to gene acquisition and provide a rare example in which demonstrable physiological traits have been correlated to the fine-scale phylogenetic architecture of an environmental bacterial community.
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developing a new resource for drug Discovery marine actinomycete bacteria
Nature Chemical Biology, 2006Co-Authors: William Fenical, Paul R. JensenAbstract:Natural Products are both a fundamental source of new chemical diversity and an integral component of today's pharmaceutical compendium. Yet interest in Natural-Product drug Discovery has waned, in part owing to diminishing returns from traditional resources such as soil bacteria. The oceans cover 70% of the Earth's surface and harbor most of the planet's biodiversity. Although marine plants and invertebrates have received considerable attention as a resource for Natural-Product Discovery, the microbiological component of this diversity remains relatively unexplored. Recent studies have revealed that select groups of marine actinomycetes are a robust source of new Natural Products. Members of the genus Salinispora have proven to be a particularly rich source of new chemical structures, including the potent proteasome inhibitor salinosporamide A, and other distinct groups are yielding new classes of terpenoids, amino acid–derived metabolites and polyene macrolides. The continued development of improved cultivation methods and technologies for accessing deep-sea environments promises to provide access to this significant new source of chemical diversity.
Marnix H Medema - One of the best experts on this subject based on the ideXlab platform.
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Ecology and genomics of Actinobacteria: new concepts for Natural Product Discovery
Nature Reviews Microbiology, 2020Co-Authors: Doris A Van Bergeijk, Marnix H Medema, Barbara R Terlouw, Gilles P Van WezelAbstract:Actinobacteria are versatile producers of bioactive Natural Products. In this Review, van Wezel and colleagues discuss ecological and genomic insights into the mechanisms governing Natural Product metabolism and how those insights can be translated into approaches for computational and experimental genome mining strategies that yield novel bioactive molecules, in particular antibiotics. Actinobacteria constitute a highly diverse bacterial phylum with an unrivalled metabolic versatility. They produce most of the clinically used antibiotics and a plethora of other Natural Products with medical or agricultural applications. Modern ‘omics’-based technologies have revealed that the genomic potential of Actinobacteria greatly outmatches the known chemical space. In this Review, we argue that combining insights into actinobacterial ecology with state-of-the-art computational approaches holds great promise to unlock this unexplored reservoir of actinobacterial metabolism. This enables the identification of small molecules and other stimuli that elicit the induction of poorly expressed biosynthetic gene clusters, which should help reinvigorate screening efforts for their precious bioactive Natural Products.
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ecology and genomics of actinobacteria new concepts for Natural Product Discovery
Nature Reviews Microbiology, 2020Co-Authors: Doris A Van Bergeijk, Marnix H Medema, Barbara R Terlouw, Gilles P Van WezelAbstract:Actinobacteria constitute a highly diverse bacterial phylum with an unrivalled metabolic versatility. They produce most of the clinically used antibiotics and a plethora of other Natural Products with medical or agricultural applications. Modern 'omics'-based technologies have revealed that the genomic potential of Actinobacteria greatly outmatches the known chemical space. In this Review, we argue that combining insights into actinobacterial ecology with state-of-the-art computational approaches holds great promise to unlock this unexplored reservoir of actinobacterial metabolism. This enables the identification of small molecules and other stimuli that elicit the induction of poorly expressed biosynthetic gene clusters, which should help reinvigorate screening efforts for their precious bioactive Natural Products.
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computational genomics of specialized metabolism from Natural Product Discovery to microbiome ecology
mSystems, 2018Co-Authors: Marnix H MedemaAbstract:ABSTRACT Microbial and plant specialized metabolites, also known as Natural Products, are key mediators of microbe-microbe and host-microbe interactions and constitute a rich resource for drug development. In the past decade, genome mining has emerged as a prominent strategy for Natural Product Discovery. Initially, such mining was performed on the basis of individual microbial genome sequences. Now, these efforts are being scaled up to fully genome-sequenced strain collections, pangenomes of bacterial genera, and large sets of metagenome-assembled genomes from microbial communities. The Medema research group aims to play a leading role in these developments by developing and applying computational approaches to identify, classify, and prioritize specialized metabolite biosynthetic gene clusters and pathways and to connect them to specific molecules and microbiome-associated phenotypes. Moreover, we are extending the scope of genome mining from microbes to plants, which will allow more comprehensive interpretation of the chemical language between hosts and microbes in a microbiome setting.
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plantismash automated identification annotation and expression analysis of plant biosynthetic gene clusters
Nucleic Acids Research, 2017Co-Authors: Satria A Kautsar, Hernando Suarez G Duran, Kai Blin, Anne Osbourn, Marnix H MedemaAbstract:Plant specialized metabolites are chemically highly diverse, play key roles in host-microbe interactions, have important nutritional value in crops and are frequently applied as medicines. It has recently become clear that plant biosynthetic pathway-encoding genes are sometimes densely clustered in specific genomic loci: biosynthetic gene clusters (BGCs). Here, we introduce plantiSMASH, a versatile online analysis platform that automates the identification of candidate plant BGCs. Moreover, it allows integration of transcriptomic data to prioritize candidate BGCs based on the coexpression patterns of predicted biosynthetic enzyme-coding genes, and facilitates comparative genomic analysis to study the evolutionary conservation of each cluster. Applied on 48 high-quality plant genomes, plantiSMASH identifies a rich diversity of candidate plant BGCs. These results will guide further experimental exploration of the nature and dynamics of gene clustering in plant metabolism. Moreover, spurred by the continuing decrease in costs of plant genome sequencing, they will allow genome mining technologies to be applied to plant Natural Product Discovery. The plantiSMASH web server, precalculated results and source code are freely available from http://plantismash.secondarymetabolites.org.
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computational strategies for genome based Natural Product Discovery and engineering in fungi
Fungal Genetics and Biology, 2016Co-Authors: Theo Van Der Lee, Marnix H MedemaAbstract:Fungal Natural Products possess biological activities that are of great value to medicine, agriculture and manufacturing. Recent metagenomic studies accentuate the vastness of fungal taxonomic diversity, and the accompanying specialized metabolic diversity offers a great and still largely untapped resource for Natural Product Discovery. Although fungal Natural Products show an impressive variation in chemical structures and biological activities, their biosynthetic pathways share a number of key characteristics. First, genes encoding successive steps of a biosynthetic pathway tend to be located adjacently on the chromosome in biosynthetic gene clusters (BGCs). Second, these BGCs are often are located on specific regions of the genome and show a discontinuous distribution among evolutionarily related species and isolates. Third, the same enzyme (super)families are often involved in the Production of widely different compounds. Fourth, genes that function in the same pathway are often co-regulated, and therefore co-expressed across various growth conditions. In this mini-review, we describe how these partly interlinked characteristics can be exploited to computationally identify BGCs in fungal genomes and to connect them to their Products. Particular attention will be given to novel algorithms to identify unusual classes of BGCs, as well as integrative pan-genomic approaches that use a combination of genomic and metabolomic data for parallelized Natural Product Discovery across multiple strains. Such novel technologies will not only expedite the Natural Product Discovery process, but will also allow the assembly of a high-quality toolbox for the re-design or even de novo design of biosynthetic pathways using synthetic biology approaches.
Sang Yup Lee - One of the best experts on this subject based on the ideXlab platform.
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synthetic biology and metabolic engineering of actinomycetes for Natural Product Discovery
Biotechnology Advances, 2019Co-Authors: E Palazzotto, Yaojun Tong, Sang Yup Lee, Tilmann WeberAbstract:Actinomycetes are one of the most valuable sources of Natural Products with industrial and medicinal importance. After more than half a century of exploitation, it has become increasingly challenging to find novel Natural Products with useful properties as the same known compounds are often repeatedly re-discovered when using traditional approaches. Modern genome mining approaches have led to the Discovery of new biosynthetic gene clusters, thus indicating that actinomycetes still harbor a huge unexploited potential to produce novel Natural Products. In recent years, innovative synthetic biology and metabolic engineering tools have greatly accelerated the Discovery of new Natural Products and the engineering of actinomycetes. In the first part of this review, we outline the successful application of metabolic engineering to optimize Natural Product Production, focusing on the use of multi-omics data, genome-scale metabolic models, rational approaches to balance precursor pools, and the engineering of regulatory genes and regulatory elements. In the second part, we summarize the recent advances of synthetic biology for actinomycetal metabolic engineering including cluster assembly, cloning and expression, CRISPR/Cas9 technologies, and chassis strain development for Natural Product overProduction and Discovery. Finally, we describe new advances in reprogramming biosynthetic pathways through polyketide synthase and non-ribosomal peptide synthetase engineering. These new developments are expected to revitalize Discovery and development of new Natural Products with medicinal and other industrial applications.
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crispr cas based genome engineering in Natural Product Discovery
Natural Product Reports, 2019Co-Authors: Yaojun Tong, Tilmann Weber, Sang Yup LeeAbstract:Covering: up to February, 2018 This review briefly introduces and summarizes current knowledge about the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas) – CRISPR/Cas system and how it was engineered to become one of the most important and versatile genome editing techniques that are currently revolutionizing the whole field of molecular biology. It aims to highlight and discuss the applications and remaining challenges of CRISPR/Cas (mainly focusing on CRISPR/SpCas9)-based genome editing in Natural Product Discovery. The organisms covered include bacteria such as Streptomyces, Corynebacteria, and Myxobacteria; filamentous fungi such as Aspergillus, Beauveria, and Ganoderma; microalgae; and some plants. As closing remarks, the prospects of using CRISPR/Cas in Natural Product Discovery will be discussed.
