scholarly journals Extremophilic Fungi from Marine Environments: Underexplored Sources of Antitumor, Anti-Infective and Other Biologically Active Agents

Marine Drugs ◽  
2022 ◽  
Vol 20 (1) ◽  
pp. 62
Author(s):  
Lesley-Ann Giddings ◽  
David J. Newman
Keyword(s):  
Natural Products ◽  
Antitumor Agents ◽  
Marine Fungi ◽  
Gene Clusters ◽  
Biologically Active ◽  
Bioactive Metabolites ◽  
Marine Environments ◽  
Environmental Pressures ◽  
Symbiotic Associations ◽  
Extremophilic Fungi

Marine environments are underexplored terrains containing fungi that produce a diversity of natural products given unique environmental pressures and nutrients. While bacteria are commonly the most studied microorganism for natural products in the marine world, marine fungi are also abundant but remain an untapped source of bioactive metabolites. Given that their terrestrial counterparts have been a source of many blockbuster antitumor agents and anti-infectives, including camptothecin, the penicillins, and cyclosporin A, marine fungi also have the potential to produce new chemical scaffolds as leads to potential drugs. Fungi are more phylogenetically diverse than bacteria and have larger genomes that contain many silent biosynthetic gene clusters involved in making bioactive compounds. However, less than 5% of all known fungi have been cultivated under standard laboratory conditions. While the number of reported natural products from marine fungi is steadily increasing, their number is still significantly lower compared to those reported from their bacterial counterparts. Herein, we discuss many varied cytotoxic and anti-infective fungal metabolites isolated from extreme marine environments, including symbiotic associations as well as extreme pressures, temperatures, salinity, and light. We also discuss cultivation strategies that can be used to produce new bioactive metabolites or increase their production. This review presents a large number of reported structures though, at times, only a few of a large number of related structures are shown.

The Fungal Metabolites with Potential Antiplasmodial Activity

2018 ◽  
Vol 25 (31) ◽  
pp. 3796-3825 ◽  
Author(s):  
Bin Yang ◽  
Jingxia Huang ◽  
Xuefeng Zhou ◽  
Xiuping Lin ◽  
Juan Liu ◽  
...  
Keyword(s):  
Natural Products ◽  
Antimicrobial Agents ◽  
Antimalarial Activity ◽  
Management Strategies ◽  
Marine Fungus ◽  
Chemical Diversity ◽  
Biologically Active ◽  
Antiplasmodial Activity ◽  
Marine Environments ◽  
Tropical Regions

Malaria caused by Plasmodium parasites is amongst many prevalent public health concerns in several tropical regions of the world. Nowadays, the parasite resistance patterns to most currently used drugs in therapy and insecticides have created an urgent need for new chemical entities exhibiting new modes of action and management strategies. Fungus has been proven to be an excellent source of biologically active compounds, which have been screened for antiplasmodial activity as potential sources of new antimalarial drugs. This review summarizes the current 255 natural products from fungus, which may possess antimalarial activity and can be classified as sesquiterpenes, diterpenes, sesterterpenes, alkaloids, peptides depsipeptides, xanthones, anthraquinones, anthrones, bioxanthracenes, bixanthones, preussomerins, depsidones, phenols, trichothecenes, azaphliones, macrolides, and steroids. However, the treatments available for malaria are limited. Thus, the identification of novel antimicrobial agents should be continued, and all possible strategies should be explored. Carrying forward the antimalarial screening in exited terrestrial and marine natural products library, and finding the new natural products in new resources, particularly those living in marine environments, are still important approaches to find new antimalarial agents. Unusual marine environments are associated with chemical diversity, leading to a resource of novel active substances for the development of bioactive products. Finding new antimalarial natural products in marine fungus, particularly those living in deep-sea and special marine environments, is an important approach to identify novel active agents.

scholarly journals Artificial Chromosomes to Explore and to Exploit Biosynthetic Capabilities of Actinomycetes

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Rosa Alduina ◽  
Giuseppe Gallo
Keyword(s):  
Secondary Metabolites ◽  
Antitumor Agents ◽  
Genetic Manipulation ◽  
Gene Clusters ◽  
Complex Compounds ◽  
Biologically Active ◽  
Biosynthetic Gene Clusters ◽  
Artificial Chromosomes ◽  
Pharmacokinetic Properties ◽  
New Strategies

Actinomycetes are an important source of biologically active compounds, like antibiotics, antitumor agents, and immunosuppressors. Genome sequencing is revealing that this class of microorganisms has larger genomes relative to other bacteria and uses a considerable fraction of its coding capacity (5–10%) for the production of mostly cryptic secondary metabolites. To access actinomycetes biosynthetic capabilities or to improve the pharmacokinetic properties and production yields of these chemically complex compounds, genetic manipulation of the producer strains can be performed. Heterologous expression in amenable hosts can be useful to exploit and to explore the genetic potential of actinomycetes and not cultivable but interesting bacteria. Artificial chromosomes that can be stably integrated into theStreptomycesgenome were constructed and demonstrated to be effective for transferring entire biosynthetic gene clusters from intractable actinomycetes into more suitable hosts. In this paper, the construction of several shuttleEscherichia coli-Streptomycesartificial chromosomes is discussed together with old and new strategies applied to improve heterologous production of secondary metabolites.

scholarly journals A Pseudoalteromonas clade with remarkable biosynthetic potential

2021 ◽  
Author(s):  
Rocky Chau ◽  
Leanne A. Pearson ◽  
Jesse Cain ◽  
John A. Kalaitzis ◽  
Brett A. Neilan
Keyword(s):  
Natural Products ◽  
Gene Cluster ◽  
Genome Mining ◽  
Gene Clusters ◽  
Average Density ◽  
Biologically Active ◽  
Biosynthesis Gene Cluster ◽  
Diverse Range ◽  
Siderophore Biosynthesis ◽  
Biosynthesis Gene

Pseudoalteromonas species produce a diverse range of biologically active compounds, including those biosynthesized by non-ribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). Here we report the biochemical and genomic analysis of Pseudoalteromonas sp. HM-SA03, isolated from the blue-ringed octopus, Hapalochalaena sp. Genome mining for secondary metabolite pathways revealed seven putative NRPS/PKS biosynthesis gene clusters, including those for the biosynthesis of alterochromides, pseudoalterobactins, alteramides and four hitherto novel compounds. Among these was a novel siderophore biosynthesis gene cluster with unprecedented architecture (NRPS-PKS-NRPS-PKS-NRPS-PKS-NRPS). Alterochromide production in HM-SA03 was also confirmed by liquid chromatography-mass spectrometry. An investigation of the biosynthetic potential of 42 publicly available Pseudoalteromonas genomes indicated that some of these gene clusters are distributed throughout the genus. Through phylogenetic analysis, a particular subset of strains formed a clade with extraordinary biosynthetic potential, with an average density of ten biosynthesis gene clusters per genome. In contrast, the majority of Pseudoalteromonas strains outside this clade contained an average of three clusters encoding complex biosynthesis. These results highlight the under-explored potential of Pseudoalteromonas as a source of new natural products. Importance This study demonstrates that the Pseudoalteromonas strain, HM-SA03, isolated from the venomous blue-ringed octopus, Hapalochalaena sp., is a biosynthetically talented organism, capable of producing alterochromides and potentially six other specialized metabolites. We have identified a pseudoalterobactin biosynthesis gene cluster and proposed a pathway for the production of the associated siderophore. A novel siderophore biosynthesis gene cluster with unprecedented architecture was also identified in the HM-SA03 genome. Finally, we have demonstrated that HM-SA03 belongs to a phylogenetic clade of strains with extraordinary biosynthetic potential. While our results do not support a role of HM-SA03 in Hapalochalaena sp. venom (tetrodotoxin) production, they emphasize the untapped potential of Pseudoalteromonas as a source of novel natural products.

scholarly journals Structure elucidation and biosynthesis of fuscachelins, peptide siderophores from the moderate thermophileThermobifida fusca

2008 ◽  
Vol 105 (40) ◽  
pp. 15311-15316 ◽  
Author(s):  
Eric J. Dimise ◽  
Paul F. Widboom ◽  
Steven D. Bruner
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Gene Cluster ◽  
Structure Elucidation ◽  
Biochemical Characterization ◽  
Gene Clusters ◽  
Biologically Active ◽  
Biosynthetic Gene ◽  
Nonribosomal Peptide

Bacteria belonging to the order Actinomycetales have proven to be an important source of biologically active and often therapeutically useful natural products. The characterization of orphan biosynthetic gene clusters is an emerging and valuable approach to the discovery of novel small molecules. Analysis of the recently sequenced genome of the thermophilic actinomyceteThermobifida fuscarevealed an orphan nonribosomal peptide biosynthetic gene cluster coding for an unknown siderophore natural product.T. fuscais a model organism for the study of thermostable cellulases and is a major degrader of plant cell walls. Here, we report the isolation and structure elucidation of the fuscachelins, siderophore natural products produced byT. fusca. In addition, we report the purification and biochemical characterization of the termination module of the nonribosomal peptide synthetase. Biochemical analysis of adenylation domain specificity supports the assignment of this gene cluster as the producer of the fuscachelin siderophores. The proposed nonribosomal peptide biosynthetic pathway exhibits several atypical features, including a macrocyclizing thioesterase that produces a 10-membered cyclic depsipeptide and a nonlinear assembly line, resulting in the unique heterodimeric architecture of the siderophore natural product.

scholarly journals Recent developments of tools for genome and metabolome studies in basidiomycete fungi and their application to natural product research

Biology Open ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. bio056010
Author(s):  
Fabrizio Alberti ◽  
Saraa Kaleem ◽  
Jack A. Weaver
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Gene Clusters ◽  
Bioactive Metabolites ◽  
Network Analyses ◽  
Natural Product Research ◽  
Technological Advances ◽  
Long Read ◽  
Recent Developments ◽  
Basidiomycete Fungi

ABSTRACTBasidiomycota are a large and diverse phylum of fungi. They can make bioactive metabolites that are used or have inspired the synthesis of antibiotics and agrochemicals. Terpenoids are the most abundant class of natural products encountered in this taxon. Other natural product classes have been described, including polyketides, peptides, and indole alkaloids. The discovery and study of natural products made by basidiomycete fungi has so far been hampered by several factors, which include their slow growth and complex genome architecture. Recent developments of tools for genome and metabolome studies are allowing researchers to more easily tackle the secondary metabolome of basidiomycete fungi. Inexpensive long-read whole-genome sequencing enables the assembly of high-quality genomes, improving the scaffold upon which natural product gene clusters can be predicted. CRISPR/Cas9-based engineering of basidiomycete fungi has been described and will have an important role in linking natural products to their genetic determinants. Platforms for the heterologous expression of basidiomycete genes and gene clusters have been developed, enabling natural product biosynthesis studies. Molecular network analyses and publicly available natural product databases facilitate data dereplication and natural product characterisation. These technological advances combined are prompting a revived interest in natural product discovery from basidiomycete fungi.This article has an associated Future Leader to Watch interview with the first author of the paper.

scholarly journals Engineering of Streptomyces lividans for heterologous expression of secondary metabolite gene clusters

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Yousra Ahmed ◽  
Yuriy Rebets ◽  
Marta Rodríguez Estévez ◽  
Josef Zapp ◽  
Maksym Myronovskyi ◽  
...  
Keyword(s):  
Natural Products ◽  
Heterologous Expression ◽  
Secondary Metabolite ◽  
Parental Strain ◽  
Genomic Library ◽  
Gene Clusters ◽  
Genetically Engineered ◽  
Biologically Active ◽  
Endogenous Gene ◽  
Site Specific Integration

Abstract Background Heterologous expression of secondary metabolite gene clusters is used to achieve increased production of desired compounds, activate cryptic gene clusters, manipulate clusters from genetically unamenable strains, obtain natural products from uncultivable species, create new unnatural pathways, etc. Several Streptomyces species are genetically engineered for use as hosts for heterologous expression of gene clusters. S. lividans TK24 is one of the most studied and genetically tractable actinobacteria, which remain untapped. It was therefore important to generate S. lividans chassis strains with clean metabolic backgrounds. Results In this study, we generated a set of S. lividans chassis strains by deleting endogenous gene clusters and introducing additional φC31 attB loci for site-specific integration of foreign DNA. In addition to the simplified metabolic background, the engineered S. lividans strains had better growth characteristics than the parental strain in liquid production medium. The utility of the developed strains was validated by expressing four secondary metabolite gene clusters responsible for the production of different classes of natural products. Engineered strains were found to be superior to the parental strain in production of heterologous natural products. Furthermore, S. lividans-based strains were better producers of amino acid-based natural products than other tested common hosts. Expression of a Streptomyces albus subsp. chlorinus NRRL B-24108 genomic library in the modified S. lividans ΔYA9 and S. albus Del14 strains resulted in the production of 7 potentially new compounds, only one of which was produced in both strains. Conclusion The constructed S. lividans-based strains are a great complement to the panel of heterologous hosts for actinobacterial secondary metabolite gene expression. The expansion of the number of such engineered strains will contribute to an increased success rate in isolation of new natural products originating from the expression of genomic and metagenomic libraries, thus raising the chance to obtain novel biologically active compounds.

scholarly journals Recent Advances in the Heterologous Biosynthesis of Natural Products from Streptomyces

2021 ◽  
Vol 11 (4) ◽  
pp. 1851
Author(s):  
Van Thuy Thi Pham ◽  
Chung Thanh Nguyen ◽  
Dipesh Dhakal ◽  
Hue Thi Nguyen ◽  
Tae-Su Kim ◽  
...  
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Heterologous Expression ◽  
Antitumor Agents ◽  
Genome Mining ◽  
Gene Clusters ◽  
Biosynthetic Gene Clusters ◽  
Heterologous Biosynthesis ◽  
Promoter Replacement ◽  
Production Platform

Streptomyces is a significant source of natural products that are used as therapeutic antibiotics, anticancer and antitumor agents, pesticides, and dyes. Recently, with the advances in metabolite analysis, many new secondary metabolites have been characterized. Moreover, genome mining approaches demonstrate that many silent and cryptic biosynthetic gene clusters (BGCs) and many secondary metabolites are produced in very low amounts under laboratory conditions. One strain many compounds (OSMAC), overexpression/deletion of regulatory genes, ribosome engineering, and promoter replacement have been utilized to activate or enhance the production titer of target compounds. Hence, the heterologous expression of BGCs by transferring to a suitable production platform has been successfully employed for the detection, characterization, and yield quantity production of many secondary metabolites. In this review, we introduce the systematic approach for the heterologous production of secondary metabolites from Streptomyces in Streptomyces and other hosts, the genome analysis tools, the host selection, and the development of genetic control elements for heterologous expression and the production of secondary metabolites.

Biologically active natural products from Cassine viburnifolia

Planta Medica ◽  
2015 ◽  
Vol 81 (11) ◽  
Author(s):  
T Grkovic ◽  
R Akee ◽  
J Evans ◽  
JM Collins ◽  
B O'Keefe
Keyword(s):  
Natural Products ◽  
Biologically Active ◽  
Active Natural
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