scholarly journals Genome mining and UHPLC-MS/MS illuminate the specificity of secondary metabolite synthetic gene clusters in Bacillus subtilis NCD-2

2020 ◽  
Author(s):  
Zhenhe Su ◽  
Xiuye Chen ◽  
Xiaomeng Liu ◽  
Qinggang Guo ◽  
Shezeng Li ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Secondary Metabolites ◽  
Secondary Metabolite ◽  
Biological Activities ◽  
Genome Mining ◽  
Gene Clusters ◽  
Synthetic Gene ◽  
Integrative Approach ◽  
Amino Acid Sequence Similarity ◽  
Genetic Characteristics

Abstract Background Bacillus subtilisstrain NCD-2 is anexcellent biocontrol agent against plant soil-borne diseases and shows broad-spectrum antifungal activities. This study aimed to explore all the secondary metabolite synthetic gene clusters and related bioactive compounds in NCD-2. An integrative approach, which coupled genome mining with structural identification technologies using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry (UHPLC-MS/MS), was conducted to interpret the chemical origins of the significant biological activities in NCD-2. Results Genome mining revealed that NCD-2 contained nine gene clustershaving predicted functionsinvolving secondary metabolites with bioactive abilities. They encoded six known products-fengycin, surfactin, bacillaene, subtilosin, bacillibactin, and bacilysin-as well as three unknown products.Interestingly, the synthetic gene clusters for surfactin and fengycin showed 83% and 92% amino acid sequence similarity levels with the corresponding productsin Bacillus velezensisstrain FZB42. A further comparison of gene clusters encoding fengycin and surfactinrevealed that strain NCD-2 had lost thefenC and fenDgenes in the fengycinbiosynthetic operon, and that the surfactin synthetic enzyme-related gene srfAB was divided into two parts.Abioinformatics analysis showed that fenEAmay function as fenCD in synthesizing fengycinand that the structure of thisfengycin synthetic gene clusteris likely unique to NCD-2.Five kinds of fengycin,with 26 homologs, and surfactin,with 4 homologs,were detectedfrom strain NCD-2, which indicated the non-typical and unique nature of this fengycin biosynthetic gene cluster.To the best of our knowledge, this is the first report of a non-typical gene cluster related to fengycin synthesis. Conclusions The data provide the genetic characteristics of secondary metabolite synthetic gene clusters for fengycinand surfactin in B. subtilis NCD-2, including the unique synthetic mechanism for fengycin, and suggest that bioactive secondary metabolites explain the biological activities of NCD-2.

scholarly journals Genome mining and UHPLC–QTOF–MS/MS illuminate the potential antimicrobial active compounds and specificity of biosynthetic gene clusters in Bacillus subtilis NCD-2

2020 ◽  
Author(s):  
Zhenhe Su ◽  
Xiuye Chen ◽  
Xiaomeng Liu ◽  
Qinggang Guo ◽  
Shezeng Li ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Gene Cluster ◽  
Biological Activities ◽  
Genome Mining ◽  
Gene Clusters ◽  
Integrative Approach ◽  
Amino Acid Sequence Similarity ◽  
Subtilis Strain ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters

Abstract Background Bacillus subtilis strain NCD-2 is an excellent biocontrol agent against plant soil-borne diseases and shows broad-spectrum antifungal activities. This study aimed to explore some of the secondary metabolite biosynthetic gene clusters and related bioactive compounds in strain NCD-2. An integrative approach, which combined genome mining with structural identification technologies using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry (UHPLC-MS/MS), was conducted to interpret the chemical origins of the significant biological activities in strain NCD-2. Results Genome mining revealed that strain NCD-2 contained nine gene clusters having predicted functions involving secondary metabolites with bioactive abilities. They encoded six known products including fengycin, surfactin, bacillaene, subtilosin, bacillibactin, bacilysin and three unknown products. Fengycin, surfactin, bacillaene and bacillibactin were successfully detected from the fermentation broth of strain NCD-2 by UHPLC-QTOF-MS/MS. Bacillaene, subtilosin, bacillibactin, and bacilysin related biosynthetic gene clusters showed 100% amino acid sequence similarity with B. velezensis strain FZB42，however, the biosynthetic gene clusters for surfactin and fengycin showed 83% and 92%, respectively. Further comparison of gene clusters encoding fengycin and surfactin revealed that strain NCD-2 had lost the fenC and fenD genes in the fengycin biosynthetic operon. Moreover, biosynthetic enzyme-related gene srfAB for surfactin had divided into two parts. Bioinformatics analysis predicted that FenE function in strain NCD-2 was same to that of FenE and FenC in strain FZB42, and FenA function in strain NCD-2 was same to that of FenA and FenD in strain FZB42. Five kinds of fengycin, with 26 homologs, and surfactin, with 4 homologs, were detected from strain NCD-2. To the best of our knowledge, this is the first report of a non-typical and unique gene cluster related to fengycin synthesis. Conclusions It was found that there were many gene clusters encoding antimicrobial compounds in the genome of strain NCD-2, and the fengycin synthetic gene cluster might be unique by using genome mining and UHPLC–QTOF–MS/MS. The production of fengycin, surfactin, bacillaene and bacillibactin might explain the biological activities of strain NCD-2.

scholarly journals Genome mining and UHPLC–QTOF–MS/MS to identify the potential antimicrobial compounds and determine the specificity of biosynthetic gene clusters in Bacillus subtilis NCD-2

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhenhe Su ◽  
Xiuye Chen ◽  
Xiaomeng Liu ◽  
Qinggang Guo ◽  
Shezeng Li ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Gene Cluster ◽  
Biological Activities ◽  
Genome Mining ◽  
Gene Clusters ◽  
Integrative Approach ◽  
Antimicrobial Compounds ◽  
Biosynthetic Gene ◽  
Similar Function ◽  
Biosynthetic Gene Clusters

Abstract Background Bacillus subtilis strain NCD-2 is an excellent biocontrol agent against plant soil-borne diseases and shows broad-spectrum antifungal activities. This study aimed to explore some secondary metabolite biosynthetic gene clusters and related antimicrobial compounds in strain NCD-2. An integrative approach combining genome mining and structural identification technologies using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry (UHPLC-MS/MS), was adopted to interpret the chemical origins of metabolites with significant biological activities. Results Genome mining revealed nine gene clusters encoding secondary metabolites with predicted functions, including fengycin, surfactin, bacillaene, subtilosin, bacillibactin, bacilysin and three unknown products. Fengycin, surfactin, bacillaene and bacillibactin were successfully detected from the fermentation broth of strain NCD-2 by UHPLC-QTOF-MS/MS. The biosynthetic gene clusters of bacillaene, subtilosin, bacillibactin, and bacilysin showed 100% amino acid sequence identities with those in B. velezensis strain FZB42, whereas the identities of the surfactin and fengycin gene clusters were only 83 and 92%, respectively. Further comparison revealed that strain NCD-2 had lost the fenC and fenD genes in the fengycin biosynthetic operon. The biosynthetic enzyme-related gene srfAB for surfactin was divided into two parts. Bioinformatics analysis suggested that FenE in strain NCD-2 had a similar function to FenE and FenC in strain FZB42, and that FenA in strain NCD-2 had a similar function to FenA and FenD in strain FZB42. Five different kinds of fengycins, with 26 homologs, and surfactin, with 4 homologs, were detected from strain NCD-2. To the best of our knowledge, this is the first report of a non-typical gene cluster related to fengycin synthesis. Conclusions Our study revealed a number of gene clusters encoding antimicrobial compounds in the genome of strain NCD-2, including a fengycin synthetic gene cluster that might be unique by using genome mining and UHPLC–QTOF–MS/MS. The production of fengycin, surfactin, bacillaene and bacillibactin might explain the biological activities of strain NCD-2.

scholarly journals Genome mining and UHPLC–QTOF–MS/MS to identify the potential antimicrobial compounds and determine the specificity of biosynthetic gene clusters in Bacillus subtilis NCD-2

2020 ◽  
Author(s):  
Zhenhe Su ◽  
Xiuye Chen ◽  
Xiaomeng Liu ◽  
Qinggang Guo ◽  
Shezeng Li ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Gene Cluster ◽  
Biological Activities ◽  
Genome Mining ◽  
Gene Clusters ◽  
Integrative Approach ◽  
Antimicrobial Compounds ◽  
Biosynthetic Gene ◽  
Similar Function ◽  
Biosynthetic Gene Clusters

Abstract Background: Bacillus subtilis strain NCD-2 is an excellent biocontrol agent against plant soil-borne diseases and shows broad-spectrum antifungal activities. This study aimed to explore some secondary metabolite biosynthetic gene clusters and related antimicrobial compounds in strain NCD-2. An integrative approach combining genome mining and structural identification technologies using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry (UHPLC-MS/MS), was adopted to interpret the chemical origins of metabolites with significant biological activities.Results: Genome mining revealed nine gene clusters encoding secondary metabolites with predicted functions, including fengycin, surfactin, bacillaene, subtilosin, bacillibactin, bacilysin and three unknown products. Fengycin, surfactin, bacillaene and bacillibactin were successfully detected from the fermentation broth of strain NCD-2 by UHPLC-QTOF-MS/MS. The biosynthetic gene clusters of bacillaene, subtilosin, bacillibactin, and bacilysin showed 100% amino acid sequence identities with those in B. velezensis strain FZB42, whereas the identities of the surfactin and fengycin gene clusters were only 83% and 92%, respectively. Further comparison revealed that strain NCD-2 had lost the fenC and fenD genes in the fengycin biosynthetic operon. The biosynthetic enzyme-related gene srfAB for surfactin was divided into two parts. Bioinformatics analysis suggested that FenE in strain NCD-2 had a similar function to FenE and FenC in strain FZB42, and that FenA in strain NCD-2 had a similar function to FenA and FenD in strain FZB42. Five different kinds of fengycins, with 26 homologs, and surfactin, with 4 homologs, were detected from strain NCD-2. To the best of our knowledge, this is the first report of a non-typical gene cluster related to fengycin synthesis.Conclusions: Our study revealed a number of gene clusters encoding antimicrobial compounds in the genome of strain NCD-2, including a fengycin synthetic gene cluster that might be unique by using genome mining and UHPLC–QTOF–MS/MS. The production of fengycin, surfactin, bacillaene and bacillibactin might explain the biological activities of strain NCD-2.

scholarly journals Discovery of a polybrominated aromatic secondary metabolite from a planctomycete points at an ambivalent interaction with its macroalgae host

2019 ◽  
Author(s):  
Fabian Panter ◽  
Ronald Garcia ◽  
Angela Thewes ◽  
Nestor Zaburannyi ◽  
Boyke Bunk ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolite ◽  
Biological Activities ◽  
Genome Mining ◽  
Gene Clusters ◽  
Laboratory Culture ◽  
Culture Conditions ◽  
Herbicidal Activity ◽  
Spectrometric Analysis ◽  
Plant Toxin

AbstractThe roles of the majority of bacterial secondary metabolites, especially those from uncommon sources are yet elusive even though many of these compounds show striking biological activities. To further investigate the secondary metabolite repertoire of underexploited bacterial families, we chose to analyze a novel representative of the yet untapped bacterial phylum Planctomycetes for the production of secondary metabolites under laboratory culture conditions. Development of a planctomycetal high density cultivation technique in combination with high resolution mass spectrometric analysis revealed Planctomycetales strain 10988 to produce the plant toxin 3,5 dibromo p-anisic acid. This molecule represents the first secondary metabolite reported from any planctomycete. Genome mining revealed the biosynthetic origin of this doubly brominated secondary metabolite and a biosynthesis model for the com-pound was devised. Comparison of the biosynthetic route to biosynthetic gene clusters responsible for formation of polybrominated small aromatic compounds reveals evidence for an evolutionary link, while the compound’s herbicidal activity points towards an ambivalent role of the metabolite in the planctomycetal ecosystem.

scholarly journals Genome mining and UHPLC–QTOF–MS/MS to identify the potential antimicrobial compounds and determine the specificity of biosynthetic gene clusters in Bacillus subtilis NCD-2

2020 ◽  
Author(s):  
Zhenhe Su ◽  
Xiuye Chen ◽  
Xiaomeng Liu ◽  
Qinggang Guo ◽  
Shezeng Li ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Gene Cluster ◽  
Biological Activities ◽  
Genome Mining ◽  
Gene Clusters ◽  
Integrative Approach ◽  
Antimicrobial Compounds ◽  
Biosynthetic Gene ◽  
Similar Function ◽  
Biosynthetic Gene Clusters

Abstract Background: Bacillus subtilis strain NCD-2 is an excellent biocontrol agent against plant soil-borne diseases and shows broad-spectrum antifungal activities. This study aimed to explore some secondary metabolite biosynthetic gene clusters and related antimicrobial compounds in strain NCD-2. An integrative approach combing genome mining and structural identification technologies using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry (UHPLC-MS/MS), was adopted to interpret the chemical origins of metabolites with significant biological activities.Results: Genome mining revealed nine gene clusters encoding secondary metabolites with predicted functions, including fengycin, surfactin, bacillaene, subtilosin, bacillibactin, bacilysin and three unknown products. Fengycin, surfactin, bacillaene and bacillibactin were successfully detected from the fermentation broth of strain NCD-2 by UHPLC-QTOF-MS/MS. The biosynthetic gene clusters of bacillaene, subtilosin, bacillibactin, and bacilysin showed 100% amino acid sequence identities with those in B. velezensis strain FZB42, whereas the identities of the surfactin and fengycin gene clusters were only 83% and 92%, respectively. Further comparison revealed that strain NCD-2 had lost the fenC and fenD genes in the fengycin biosynthetic operon. The biosynthetic enzyme-related gene srfAB for surfactin was divided into two parts. Bioinformatics analysis suggested that FenE in strain NCD-2 had a similar function to FenE and FenC in strain FZB42, and that FenA in strain NCD-2 had a similar function to FenA and FenD in strain FZB42. Five different kinds of fengycins, with 26 homologs, and surfactin, with 4 homologs, were detected from strain NCD-2. To the best of our knowledge, this is the first report of a non-typical gene cluster related to fengycin synthesis.Conclusions: Our study revealed a number of gene clusters encoding antimicrobial compounds in the genome of strain NCD-2, including a fengycin synthetic gene cluster that might be unique by using genome mining and UHPLC–QTOF–MS/MS. The production of fengycin, surfactin, bacillaene and bacillibactin might explain the biological activities of strain NCD-2.

scholarly journals Phylogenetic Distribution of Secondary Metabolites in the Bacillus subtilis Species Complex

mSystems ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Kat Steinke ◽  
Omkar S. Mohite ◽  
Tilmann Weber ◽  
Ákos T. Kovács
Keyword(s):  
Bacillus Subtilis ◽  
Secondary Metabolites ◽  
Secondary Metabolite ◽  
Species Complex ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Content Type ◽  
Frameshift Mutations ◽  
Metabolite Production

ABSTRACT Microbes produce a plethora of secondary (or specialized) metabolites that, although not essential for primary metabolism, benefit them to survive in the environment, communicate, and influence cell differentiation. Biosynthetic gene clusters (BGCs), responsible for the production of these secondary metabolites, are readily identifiable on bacterial genome sequences. Understanding the phylogeny and distribution of BGCs helps us to predict the natural product synthesis ability of new isolates. Here, we examined 310 genomes from the Bacillus subtilis group, determined the inter- and intraspecies patterns of absence/presence for all BGCs, and assigned them to defined gene cluster families (GCFs). This allowed us to establish patterns in the distribution of both known and unknown products. Further, we analyzed variations in the BGC structures of particular families encoding natural products, such as plipastatin, fengycin, iturin, mycosubtilin, and bacillomycin. Our detailed analysis revealed multiple GCFs that are species or clade specific and a few others that are scattered within or between species, which will guide exploration of the chemodiversity within the B. subtilis group. Surprisingly, we discovered that partial deletion of BGCs and frameshift mutations in selected biosynthetic genes are conserved within phylogenetically related isolates, although isolated from around the globe. Our results highlight the importance of detailed genomic analysis of BGCs and the remarkable phylogenetically conserved erosion of secondary metabolite biosynthetic potential in the B. subtilis group. IMPORTANCE Members of the B. subtilis species complex are commonly recognized producers of secondary metabolites, among those, the production of antifungals, which makes them promising biocontrol strains. While there are studies examining the distribution of well-known secondary metabolites in Bacilli, intraspecies clade-specific distribution has not been systematically reported for the B. subtilis group. Here, we report the complete biosynthetic potential within the B. subtilis group to explore the distribution of the biosynthetic gene clusters and to reveal an exhaustive phylogenetic conservation of secondary metabolite production within Bacillus that supports the chemodiversity within this species complex. We identify that certain gene clusters acquired deletions of genes and particular frameshift mutations, rendering them inactive for secondary metabolite biosynthesis, a conserved genetic trait within phylogenetically conserved clades of certain species. The overview guides the assignment of the secondary metabolite production potential of newly isolated Bacillus strains based on genome sequence and phylogenetic relatedness.

scholarly journals Genome mining of a marine-derived Streptomyces sp. PDH23 isolated from sponge in Da Nang sea for secondary metabolite gene clusters

2021 ◽  
Vol 18 (4) ◽  
pp. 709-721
Author(s):  
Le Ngoc Giang ◽  
Le Thi Hong Minh ◽  
Vu Thi Quyen ◽  
Nguyen Mai Anh ◽  
Nguyen Thi Kim Cuc ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Antimicrobial Agents ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Genome Mining ◽  
Gc Content ◽  
Gene Clusters ◽  
Gram Positive ◽  
16S Rrna Analysis ◽  
Streptomyces Sp

The streptomyces is one of the best characterized ubiquitous filamentous bacteria from the actinobacteriaclass. They are known to produce thousands of specialized metabolite biosynthesis gene clusters (SMBG). Their SMBG clusters have multiple activities ranging from antimicrobial, antitumor, antiviral and probiotic. Streptomyces strain and their isolates with interesting biological activities against gram-positive and gram-negative indicator strains was recently characterised. Currently, they are employed in more than half of all antibiotics used in human and veterinary medicine. With the increase in drug resistance bacteria, it is important to mine for new natural chemicals.In this study, screening via disk-diffusion agar method revealed that Streptomyces sp. PDH23 isolated from the Rhabdastrellaglobostellata marine sponge sample from Da Nang, Vietnam produce antimicrobial agents with a wide spectrum of activities. This species can produce highly active enzymes, which breakdown celluloses, amyloses and proteins. On top of that they are shown to restrict the grow of the gram positive Bacillus cereus ATCC14579 (BC), Staphylococcus aureus ATCC25923 (SA), the gram-negativeVibrio parahaemolyticus ATCC17802 (VP) and the Candida albicans ATCC10231 fungus (CA). They are antimethicillin-resistant S. aureus(MRSA) ATCC33591 andmethicillin-resistantS. epidermidis (MRSE) ATCC35984. The taxonomy of PDH23 was characterized using 16S rRNA analysis. Whole genome sequencing of PDH23 showed 8594820 base pairs with GC content of 72.03%. Mining of secondary metabolites reveals gene clusters responsible for the biosynthesis of known and/or novel secondary metabolites, including different types of terpene, NRPS-like , PKS, PKS-like, hglE-KS, betalactone, melanin, t1pks, t2pks, t3pks, nrps, indole, siderophore, bacteriocin, ectoine, butyrolactone, phenazine.

scholarly journals Chromatin-dependent regulation of secondary metabolite biosynthesis in fungi: is the picture complete?

2019 ◽  
Author(s):  
Jérôme Collemare ◽  
Michael F Seidl
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolite ◽  
Biological Activities ◽  
Gene Clusters ◽  
Research Field ◽  
Chromatin Modifications ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Post Translational Modifications ◽  
Fungal Secondary Metabolites

ABSTRACTFungal secondary metabolites are small molecules that exhibit diverse biological activities exploited in medicine, industry and agriculture. Their biosynthesis is governed by co-expressed genes that often co-localize in gene clusters. Most of these secondary metabolite gene clusters are inactive under laboratory conditions, which is due to a tight transcriptional regulation. Modifications of chromatin, the complex of DNA and histone proteins influencing DNA accessibility, play an important role in this regulation. However, tinkering with well-characterised chemical and genetic modifications that affect chromatin alters the expression of only few biosynthetic gene clusters, and thus the regulation of the vast majority of biosynthetic pathways remains enigmatic. In the past, attempts to activate silent gene clusters in fungi mainly focused on histone acetylation and methylation, while in other eukaryotes many other post-translational modifications are involved in transcription regulation. Thus, how chromatin regulates the expression of gene clusters remains a largely unexplored research field. In this review, we argue that focusing on only few well-characterised chromatin modifications is significantly hampering our understanding of the chromatin-based regulation of biosynthetic gene clusters. Research on underexplored chromatin modifications and on the interplay between different modifications is timely to fully explore the largely untapped reservoir of fungal secondary metabolites.

scholarly journals Secondary Metabolite Production Potential of Mangrove-Derived Streptomyces olivaceus

Marine Drugs ◽  
2021 ◽  
Vol 19 (6) ◽  
pp. 332
Author(s):  
Dini Hu ◽  
Simon Ming-Yuen Lee ◽  
Kai Li ◽  
Kai Meng Mok
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolite ◽  
Fermentation Broth ◽  
Genome Mining ◽  
Extreme Environments ◽  
Gene Clusters ◽  
Secondary Metabolite Production ◽  
Production Potential ◽  
Metabolite Production ◽  
Streptomyces Olivaceus

Mangroves are intertidal extreme environments with rich microbial communities. Actinobacteria are well known for producing antibiotics. The search for biosynthetic potential of Actinobacteria from mangrove environments could provide more possibilities for useful secondary metabolites. In this study, whole genome sequencing and MS/MS analysis were used to explore the secondary metabolite production potential of one actinobacterial strain of Streptomyces olivaceus sp., isolated from a mangrove in Macau, China. The results showed that a total of 105 gene clusters were found in the genome of S. olivaceus sp., and 53 known secondary metabolites, including bioactive compounds, peptides, and other products, were predicted by genome mining. There were 28 secondary metabolites classified as antibiotics, which were not previously known from S. olivaceus. ISP medium 2 was then used to ferment the S. olivaceus sp. to determine which predicted secondary metabolite could be truly produced. The chemical analysis revealed that ectoine, melanin, and the antibiotic of validamycin A could be observed in the fermentation broth. This was the first observation that these three compounds can be produced by a strain of S. olivaceus. Therefore, it can be concluded that Actinobacteria isolated from the mangrove environment have unknown potential to produce bioactive secondary metabolites.

scholarly journals Applications of CRISPR/Cas9 in the Synthesis of Secondary Metabolites in Filamentous Fungi

2021 ◽  
Vol 12 ◽  
Author(s):  
Chunmiao Jiang ◽  
Gongbo Lv ◽  
Yayi Tu ◽  
Xiaojie Cheng ◽  
Yitian Duan ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Genome Editing ◽  
Secondary Metabolite ◽  
Filamentous Fungi ◽  
Biological Activities ◽  
Genetic Research ◽  
Gene Clusters ◽  
Biologically Active ◽  
Future Application ◽  
Advanced Technique

Filamentous fungi possess the capacity to produce a wide array of secondary metabolites with diverse biological activities and structures, such as lovastatin and swainsonine. With the advent of the post-genomic era, increasing amounts of cryptic or uncharacterized secondary metabolite biosynthetic gene clusters are continually being discovered. However, owing to the longstanding lack of versatile, comparatively simple, and highly efficient genetic manipulation techniques, the broader exploration of industrially important secondary metabolites has been hampered thus far. With the emergence of CRISPR/Cas9-based genome editing technology, this dilemma may be alleviated, as this advanced technique has revolutionized genetic research and enabled the exploitation and discovery of new bioactive compounds from filamentous fungi. In this review, we introduce the CRISPR/Cas9 system in detail and summarize the latest applications of CRISPR/Cas9-mediated genome editing in filamentous fungi. We also briefly introduce the specific applications of the CRISPR/Cas9 system and CRISPRa in the improvement of secondary metabolite contents and discovery of novel biologically active compounds in filamentous fungi, with specific examples noted. Additionally, we highlight and discuss some of the challenges and deficiencies of using the CRISPR/Cas9-based genome editing technology in research on the biosynthesis of secondary metabolites as well as future application of CRISPR/Cas9 strategy in filamentous fungi are highlighted and discussed.

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