scholarly journals Fungal Endophytes: A Promising Frontier for Discovery of Novel Bioactive Compounds

2021 ◽  
Vol 7 (10) ◽  
pp. 786
Author(s):  
Martin Muthee Gakuubi ◽  
Madhaiyan Munusamy ◽  
Zhao-Xun Liang ◽  
Siew Bee Ng
Keyword(s):  
Bioactive Compounds ◽  
Host Plants ◽  
Communicable Disease ◽  
Biological Activities ◽  
Fungal Endophytes ◽  
Gene Clusters ◽  
New Drugs ◽  
Biosynthetic Gene Clusters ◽  
Fungal Isolation ◽  
Non Communicable Disease

For years, fungi have served as repositories of bioactive secondary metabolites that form the backbone of many existing drugs. With the global rise in infections associated with antimicrobial resistance, in addition to the growing burden of non-communicable disease, such as cancer, diabetes and cardiovascular ailments, the demand for new drugs that can provide an improved therapeutic outcome has become the utmost priority. The exploration of microbes from understudied and specialized niches is one of the promising ways of discovering promising lead molecules for drug discovery. In recent years, a special class of plant-associated fungi, namely, fungal endophytes, have emerged as an important source of bioactive compounds with unique chemistry and interesting biological activities. The present review focuses on endophytic fungi and their classification, rationale for selection and prioritization of host plants for fungal isolation and examples of strategies that have been adopted to induce the activation of cryptic biosynthetic gene clusters to enhance the biosynthetic potential of fungal endophytes.

scholarly journals Discovery of Cyanobacterial Natural Products Containing Fatty Acid Residues

2020 ◽  
Author(s):  
Sandra A. C. Figueiredo ◽  
Marco Preto ◽  
Gabriela Moreira ◽  
Teresa P. Martins ◽  
Kathleen Abt ◽  
...  
Keyword(s):  
Natural Products ◽  
Fatty Acid ◽  
Isotope Labeling ◽  
Gene Clusters ◽  
New Drugs ◽  
Beta Oxidation ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Apparent Lack ◽  
Massive Sequencing

Natural products have an important role in several human activities, most notably as sources of new drugs. In recent years, massive sequencing and annotation of bacterial genomes has revealed an unexpectedly large number of secondary metabolite biosynthetic gene clusters whose products are yet to be discovered. For example, cyanobacterial genomes contain a large number of gene clusters that likely incorporate fatty acid-derived moieties, but for most cases we lack the knowledge and tools to effectively predict or detect the encoded natural products. Here, we exploit the apparent lack of a functional beta-oxidation pathway in cyanobacteria to achieve efficient stable-isotope labeling of their fatty acid-derived lipidome. We show that supplementation of cyanobacterial cultures with deuterated fatty acids can be used to easily detect natural product signatures in individual strains. The utility of this strategy is demonstrated in two cultured cyanobacteria by uncovering analogues of the multidrug-resistance reverting hapalosin, and novel, cytotoxic, lactylate-nocuolin A hybrids – the nocuolactylates.

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

Chemical and Functional Diversity of Natural Products from Plant Associated Endophytic Fungi

2009 ◽  
Vol 4 (11) ◽  
pp. 1934578X0900401 ◽  
Author(s):  
Vijay C. Verma ◽  
Ravindra N. Kharwar ◽  
Gary A. Strobel
Keyword(s):  
Natural Products ◽  
Biological Activity ◽  
Functional Diversity ◽  
Bioactive Compounds ◽  
Endophytic Fungi ◽  
Host Plants ◽  
Fungal Endophytes ◽  
Sources Identification ◽  
Naturally Occurring

This review describes examples of naturally occurring bioactive compounds obtained from fungal endophytes from various host plants. The main topics addressed are sources, identification, biological activity, biosynthesis, and ecological and chemosystematic significance of those bioactive compounds whose sources were well defined.

scholarly journals BIOLOGICAL ACTIVITIES OF ALTERNARIA SP. RL4 – A POTENT ENDOPHYTIC FUNGUS ASSOCIATED WITH RAUVOLFIA SERPENTINA L. BENTH.

2018 ◽  
Vol 11 (11) ◽  
pp. 178
Author(s):  
Ranjan Ghosh ◽  
Soma Barman ◽  
Pavan Kumar Jgs ◽  
Narayan C Mandal
Keyword(s):  
Mode Of Action ◽  
Pathogenic Bacteria ◽  
Biological Activities ◽  
Fungal Endophytes ◽  
Radical Scavenging ◽  
New Drugs ◽  
Bioactive Metabolites ◽  
Gram Positive ◽  
Rauvolfia Serpentina ◽  
Alternaria Sp

Objectives: Endophytic fungi are considered as an important source of bioactive metabolites. The present study focused on the isolation of potent endophytic fungal strains from well-known medicinal plant Rauvolfia serpentina L. Benth. having biological activities.Materials & Methods: Fungal endophytes were isolated from aerial parts of the plant and the potent strain was selected on the basis of antibacterial activities of cell-free supernatant (CFS). Ethyl acetate (EA) extraction of CFS was done and mode of action of EA fraction was checked against pathogenic bacteria. EA fraction was also analyzed by thin-layer chromatography (TLC). In addition, antioxidant activity was checked by 1,1-Diphenyl- 2-picrylhydrazyl-free radical scavenging assay and anticancer activity was checked against breast cancer cell line MCF-7 by MTT assay.Results: Among the different endophytic fungal isolates, CFS of Alternaria sp. RL4 produced prominent zones of inhibition against numbers of Gram-positive pathogenic bacteria including Staphylococcus aureus (12±0.5 mm) and Listeria monocytogenes (17±2.0 mm). Massive reductions in bacterial CFS were noticed upon treatment with EA fraction (2 mg/ml). It also showed strong cidal mode of action against Gram-positive organisms. TLC analysis revealed the production of two different compounds with antibacterial potentials. In addition, EA fraction of RL4 showed very good antioxidant property with an IC50 value of 49.80±2.11μg/ml. MTT assay also suggested the anticancerous properties of EA fraction of RL4.Conclusion: Alternaria sp. RL4 could be a very good source of bioactive compounds for the development of new drugs.

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 Reclassification of the Specialized Metabolite Producer Pseudomonas mesoacidophila ATCC 31433 as a Member of the Burkholderia cepacia Complex

2017 ◽  
Vol 199 (13) ◽  
Author(s):  
E. Joel Loveridge ◽  
Cerith Jones ◽  
Matthew J. Bull ◽  
Suzy C. Moody ◽  
Małgorzata W. Kahl ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Bioactive Compounds ◽  
Single Molecule ◽  
Complete Genome ◽  
Burkholderia Cepacia ◽  
Gene Clusters ◽  
Burkholderia Cepacia Complex ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Content Type

ABSTRACT Pseudomonas mesoacidophila ATCC 31433 is a Gram-negative bacterium, first isolated from Japanese soil samples, that produces the monobactam isosulfazecin and the β-lactam-potentiating bulgecins. To characterize the biosynthetic potential of P. mesoacidophila ATCC 31433, its complete genome was determined using single-molecule real-time DNA sequence analysis. The 7.8-Mb genome comprised four replicons, three chromosomal (each encoding rRNA) and one plasmid. Phylogenetic analysis demonstrated that P. mesoacidophila ATCC 31433 was misclassified at the time of its deposition and is a member of the Burkholderia cepacia complex, most closely related to Burkholderia ubonensis. The sequenced genome shows considerable additional biosynthetic potential; known gene clusters for malleilactone, ornibactin, isosulfazecin, alkylhydroxyquinoline, and pyrrolnitrin biosynthesis and several uncharacterized biosynthetic gene clusters for polyketides, nonribosomal peptides, and other metabolites were identified. Furthermore, P. mesoacidophila ATCC 31433 harbors many genes associated with environmental resilience and antibiotic resistance and was resistant to a range of antibiotics and metal ions. In summary, this bioactive strain should be designated B. cepacia complex strain ATCC 31433, pending further detailed taxonomic characterization. IMPORTANCE This work reports the complete genome sequence of Pseudomonas mesoacidophila ATCC 31433, a known producer of bioactive compounds. Large numbers of both known and novel biosynthetic gene clusters were identified, indicating that P. mesoacidophila ATCC 31433 is an untapped resource for discovery of novel bioactive compounds. Phylogenetic analysis demonstrated that P. mesoacidophila ATCC 31433 is in fact a member of the Burkholderia cepacia complex, most closely related to the species Burkholderia ubonensis. Further investigation of the classification and biosynthetic potential of P. mesoacidophila ATCC 31433 is warranted.

scholarly journals Heterologous production of cyanobacterial compounds

2021 ◽  
Author(s):  
Dipesh Dhakal ◽  
Manyun Chen ◽  
Hendrik Luesch ◽  
Yousong Ding
Keyword(s):  
Natural Products ◽  
Genetic Engineering ◽  
Biological Activities ◽  
Rapid Development ◽  
Gene Clusters ◽  
Heterologous Production ◽  
Biosynthetic Gene Clusters ◽  
Chemical Structures ◽  
Host Genetic ◽  
Slow Growing

Abstract Cyanobacteria produce a plethora of compounds with unique chemical structures and diverse biological activities. Importantly, the increasing availability of cyanobacterial genome sequences and the rapid development of bioinformatics tools have unraveled the tremendous potential of cyanobacteria in producing new natural products. However, the discovery of these compounds based on cyanobacterial genomes has progressed slowly as the majority of their corresponding biosynthetic gene clusters (BGCs) are silent. In addition, cyanobacterial strains are often slow-growing, difficult for genetic engineering, or cannot be cultivated yet, limiting the use of host genetic engineering approaches for discovery. On the other hand, genetically tractable hosts such as Escherichia coli, Actinobacteria, and yeast have been developed for the heterologous expression of cyanobacterial BGCs. More recently, there has been increased interests in developing model cyanobacterial strains as heterologous production platforms. Herein, we present recent advances in the heterologous production of cyanobacterial compounds in both cyanobacterial and non-cyanobacterial hosts. Emerging strategies for BGC assembly, host engineering, and optimization of BGC expression are included for fostering the broader applications of synthetic biology tools in the discovery of new cyanobacterial natural products.

scholarly journals Discovery of Cyanobacterial Natural Products Containing Fatty Acid Residues

2020 ◽  
Author(s):  
Sandra A. C. Figueiredo ◽  
Marco Preto ◽  
Gabriela Moreira ◽  
Teresa P. Martins ◽  
Kathleen Abt ◽  
...  
Keyword(s):  
Natural Products ◽  
Fatty Acid ◽  
Isotope Labeling ◽  
Gene Clusters ◽  
New Drugs ◽  
Beta Oxidation ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Apparent Lack ◽  
Massive Sequencing

Natural products have an important role in several human activities, most notably as sources of new drugs. In recent years, massive sequencing and annotation of bacterial genomes has revealed an unexpectedly large number of secondary metabolite biosynthetic gene clusters whose products are yet to be discovered. For example, cyanobacterial genomes contain a large number of gene clusters that likely incorporate fatty acid-derived moieties, but for most cases we lack the knowledge and tools to effectively predict or detect the encoded natural products. Here, we exploit the apparent lack of a functional beta-oxidation pathway in cyanobacteria to achieve efficient stable-isotope labeling of their fatty acid-derived lipidome. We show that supplementation of cyanobacterial cultures with deuterated fatty acids can be used to easily detect natural product signatures in individual strains. The utility of this strategy is demonstrated in two cultured cyanobacteria by uncovering analogues of the multidrug-resistance reverting hapalosin, and novel, cytotoxic, lactylate-nocuolin A hybrids – the nocuolactylates.

scholarly journals Genomic and transcriptomic survey of an endophytic fungus Calcarisporium arbuscula NRRL 3705 and potential overview of its secondary metabolites

2019 ◽  
Author(s):  
Jintao Cheng ◽  
Fei Cao ◽  
Xinai Chen ◽  
Yongquan Li ◽  
Xuming Mao
Keyword(s):  
Secondary Metabolites ◽  
Gene Cluster ◽  
Endophytic Fungi ◽  
Single Molecule ◽  
Endophytic Fungus ◽  
Biological Activities ◽  
Housekeeping Genes ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters

Abstract Endophytic fungi can produce many active secondary metabolites, which are important resources of natural medicines. However, there is currently little understanding of endophytic fungi at the omics levels. Calcarisporium arbuscula , an endophytic fungus from the healthy fruit of russulaceae, can produce a variety of secondary metabolites with anti-cancer, anti-nematode and antibiotic bioactivities. Comprehensive survey of the endophytic fungi genome and transcriptome will help to understand their capacity to biosynthesize secondary metabolites and lay the foundation for the development of these precious resources. In this study，we reported the high-quality genome sequence of a strain C. arbuscula NRRL 3705 based on Single Molecule Real-Time sequencing technology. The genome of this fungus is over 45 Mb in size, relatively larger than other typical filamentous fungi, and comprises 10,001 predictable genes, encoding at least 762 secretory-proteins, 386 carbohydrate-active enzymes and 177 P450 enzymes. 398 virulence factors and 228 genes related to pathogen-host interactions were also predicted in this fungus. Moreover , 65 secondary metabolite biosynthetic gene clusters were revealed, including the gene cluster for mycotoxins aurovertins. In addition, several gene clusters were predicted to produce various mycotoxins, including aflatoxin, alternariol, destruxin, citrinin and isoflavipucine. Notably, two independent gene clusters were shown possibly involved in the biosynthesis of alternariol. Furthermore, RNA-Seq assay showed that only the expression of aurovertin gene cluster is much stronger than the housekeeping genes under laboratory conditions, consistent with that aurovertins are the predominant metabolites. The gene expression of the remaining 64 gene clusters for compound backbone biosynthesis was all lower than the housekeeping genes, which might partially explain poor production of other secondary metabolites in this fungus.Our omics data along with bioinformatics analysis indicated that C. arbuscula NRRL 3705 contains a large number of biosynthetic gene clusters and has a huge potential to produce profound secondary metabolites. This work also provides the basis for development of endophytic fungi as a new resource of natural products with promising biological activities.

scholarly journals BiG-SLiCE: A Highly Scalable Tool Maps the Diversity of 1.2 Million Biosynthetic Gene Clusters

2020 ◽  
Author(s):  
Satria A. Kautsar ◽  
Justin J. J. van der Hooft ◽  
Dick de Ridder ◽  
Marnix H. Medema
Keyword(s):  
Natural Product ◽  
Biological Activities ◽  
Genome Mining ◽  
Gene Clusters ◽  
Genomic Diversity ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Microbial Genomes ◽  
Natural Product Discovery ◽  
User Friendly

AbstractBackgroundGenome mining for Biosynthetic Gene Clusters (BGCs) has become an integral part of natural product discovery. The >200,000 microbial genomes now publicly available hold information on abundant novel chemistry. One way to navigate this vast genomic diversity is through comparative analysis of homologous BGCs, which allows identification of cross-species patterns that can be matched to the presence of metabolites or biological activities. However, current tools suffer from a bottleneck caused by the expensive network-based approach used to group these BGCs into Gene Cluster Families (GCFs).ResultsHere, we introduce BiG-SLiCE, a tool designed to cluster massive numbers of BGCs. By representing them in Euclidean space, BiG-SLiCE can group BGCs into GCFs in a non-pairwise, near-linear fashion. We used BiG-SLiCE to analyze 1,225,071 BGCs collected from 209,206 publicly available microbial genomes and metagenome-assembled genomes (MAGs) within ten days on a typical 36-cores CPU server. We demonstrate the utility of such analyses by reconstructing a global map of secondary metabolic diversity across taxonomy to identify uncharted biosynthetic potential. BiG-SLiCE also provides a "query mode" that can efficiently place newly sequenced BGCs into previously computed GCFs, plus a powerful output visualization engine that facilitates user-friendly data exploration.ConclusionsBiG-SLiCE opens up new possibilities to accelerate natural product discovery and offers a first step towards constructing a global, searchable interconnected network of BGCs. As more genomes get sequenced from understudied taxa, more information can be mined to highlight their potentially novel chemistry. BiG-SLiCE is available via https://github.com/medema-group/bigslice.

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