Novel Alkaloids from Marine Actinobacteria: Discovery and Characterization.
Ontology highlight
ABSTRACT:
SUBMITTER: De Rop AS
PROVIDER: S-EPMC8777666 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable target for the continued development of broadly active antiviral compounds.
| S-EPMC3857800 | biostudies-literature
Project description:Marine actinobacteriology is one of the major emerging areas of research in tropics. Marine actinobacteria occur on the sediments and in water and also other biomass (mangrove) and substrates (animal). These organisms are gaining importance not only for their taxonomic and ecological perspectives, but also for their unique metabolites and enzymes. Many earlier studies on these organisms were confined only to the temperate regions. In tropical environment, investigations on them have gained importance only in the last two decades. So far, from the Indian peninsula, 41 species of actinobacteria belonging to 8 genera have been recorded. The genus, Streptomyces of marine origin has been more frequently recorded. Of 9 maritime states of India, only 4 have been extensively covered for the study of marine actinobacteria. Most of the studies conducted pertain to isolation, identification and maintenance of these organisms in different culture media. Further, attention has been focused on studying their antagonistic properties against different pathogens. Their biotechnological potentials are yet to be fully explored.
| S-EPMC3450339 | biostudies-other
Project description:Nitrogen heterocycles have drawn considerable attention due to of their significant biological activities. The marine fungi residing in extreme environments are among the richest sources of these basic nitrogen-containing secondary metabolites. As one of the most well-known universal groups of filamentous fungi, marine-derived Aspergillus species produce a large number of structurally unique heterocyclic alkaloids. This review attempts to provide a comprehensive summary of the structural diversity and biological activities of heterocyclic alkaloids that are produced by marine-derived Aspergillus species. Herein, a total of 130 such structures that were reported from the beginning of 2014 through the end of 2018 are included, and 75 references are cited in this review, which will benefit future drug development and innovation.
| S-EPMC7024353 | biostudies-literature
Project description:Adenovirus infections in immunocompromised patients are associated with high mortality rates. Currently, there are no effective anti-adenoviral therapies available. It is well known that actinobacteria can produce secondary metabolites that are attractive in drug discovery due to their structural diversity and their evolved interaction with biomolecules. Here, we have established an extract library derived from actinobacteria isolated from Vestfjorden, Norway, and performed a screening campaign to discover anti-adenoviral compounds. One extract with anti-adenoviral activity was found to contain a diastereomeric 1:1 mixture of the butenolide secondary alcohols 1a and 1b. By further cultivation and analysis, we could isolate 1a and 1b in different diastereomeric ratio. In addition, three more anti-adenoviral butenolides 2, 3 and 4 with differences in their side-chains were isolated. In this study, the anti-adenoviral activity of these compounds was characterized and substantial differences in the cytotoxic potential between the butenolide analogs were observed. The most potent butenolide analog 3 displayed an EC50 value of 91 μM and no prominent cytotoxicity at 2 mM. Furthermore, we propose a biosynthetic pathway for these compounds based on their relative time of appearance and structure.
| S-EPMC3944516 | biostudies-literature
Project description:Cellulose is the most abounding biopolymer in the world and there is a great interest in using this material as a substrate for various applications and it is the most important renewable resource for bioconversion. Therefore, it is necessary to screen the cellulolytic bioorganisms. In this context, actinobacteria are one of the most efficient prokaryotes, economically and biotechnologically, for their production of about half of the discovered bioactive secondary metabolites and they can metabolize many different compounds. Therefore, the present study was carried out to isolate and screen cellulase enzyme producing marine actinobacterial strains from the sediments of the Havelock island, the Andamans. Totally, 19 morphologically distinct actinobacterial strains were isolated and subjected to cellulose degradation assay. Out of the 19, four strains were found to possess good cellulose degradation activity and the strain MHA15 alone produced higher amount of cellulase enzyme (14.379 1U/ml) than the others. Taxonomical study of the strain MHA15 revealed that it belongs to the genus Actinoalloteichus and the molecular characters showed distinct difference in its phylogenetic relationship (8.4%) with A. cyanogriseus.
| S-EPMC5361130 | biostudies-literature
Project description:Phylogenetic analysis of the ketosynthase (KS) gene sequences of marine sponge-derived Salinispora strains of actinobacteria indicated that the polyketide synthase (PKS) gene sequence most closely related to that of Salinispora was the rifamycin B synthase of Amycolatopsis mediterranei. This result was not expected from taxonomic species tree phylogenetics using 16S rRNA sequences. From the PKS sequence data generated from our sponge-derived Salinispora strains, we predicted that such strains might synthesize rifamycin-like compounds. Liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis was applied to one sponge-derived Salinispora strain to test the hypothesis of rifamycin synthesis. The analysis reported here demonstrates that this Salinispora isolate does produce compounds of the rifamycin class, including rifamycin B and rifamycin SV. A rifamycin-specific KS primer set was designed, and that primer set increased the number of rifamycin-positive strains detected by PCR screening relative to the number detectable using a conserved KS-specific set. Thus, the Salinispora group of actinobacteria represents a potential new source of rifamycins outside the genus Amycolatopsis and the first recorded source of rifamycins from marine bacteria.
| S-EPMC1393243 | biostudies-literature
Project description:Natural products from plants are useful as lead compounds in drug discovery. Plant benzylisoquinoline alkaloids (BIAs) exhibit various pharmaceutical activities. Although unidentified BIAs are expected to be of medicinal value, sufficient quantities of such BIAs, for biological assays, are sometimes difficult to obtain due to their low content in natural sources. Here, we showed that high productivity of BIAs in engineered Escherichia coli could be exploited for drug discovery. First, we improved upon the previous microbial production system producing (S)-reticuline, an important BIA intermediate, to obtain yields of around 160?mg/L, which was 4-fold higher than those of the previously reported highest production system. Subsequently, we synthesised non-natural BIAs (O-sulphated (S)-reticulines) by introducing human sulphotransferases into the improved (S)-reticuline production system. Analysis of human primary cells treated with these BIAs demonstrated that they affected a biomarker expression in a manner different from that by the parent compound (S)-reticuline, suggesting that simple side-chain modification altered the characteristic traits of BIA. These results indicated that highly productive microbial systems might facilitate the production of scarce or novel BIAs and enable subsequent evaluation of their biological activities. The system developed here could be applied to other rare natural products and might contribute to the drug-discovery process as a next-generation strategy.
| S-EPMC5964154 | biostudies-literature
Project description:Like many fields of the biosciences, actinomycete natural products research has been revolutionised by next-generation DNA sequencing (NGS). Hundreds of new genome sequences from actinobacteria are made public every year, many of them as a result of projects aimed at identifying new natural products and their biosynthetic pathways through genome mining. Advances in these technologies in the last five years have meant not only a reduction in the cost of whole genome sequencing, but also a substantial increase in the quality of the data, having moved from obtaining a draft genome sequence comprised of several hundred short contigs, sometimes of doubtful reliability, to the possibility of obtaining an almost complete and accurate chromosome sequence in a single contig, allowing a detailed study of gene clusters and the design of strategies for refactoring and full gene cluster synthesis. The impact that these technologies are having in the discovery and study of natural products from actinobacteria, including those from the marine environment, is only starting to be realised. In this review we provide a historical perspective of the field, analyse the strengths and limitations of the most relevant technologies, and share the insights acquired during our genome mining projects.
| S-EPMC4849082 | biostudies-literature
Project description:Predatory bacteria constitute a heterogeneous group of prokaryotes able to lyse and feed on the cellular constituents of other bacteria in conditions of nutrient scarcity. In this study, we describe the isolation of Actinobacteria predator of other bacteria from the marine water of the Moroccan Atlantic coast. Only 4 Actinobacteria isolates showing strong predation capability against native or multidrug-resistant Gram-positive or Gram-negative bacteria were identified among 142 isolated potential predatory bacteria. These actinobacterial predators were shown to belong to the Streptomyces genus and to inhibit the growth of various native or multidrug-resistant micro-organisms, including Micrococcus luteus, Staphylococcus aureus (native and methicillin-resistant), and Escherichia coli (native and ampicillin-resistant). Even if no clear correlation could be established between the antibacterial activities of the selected predator Actinobacteria and their predatory activity, we cannot exclude that some specific bio-active secondary metabolites were produced in this context and contributed to the killing and lysis of the bacteria. Indeed, the co-cultivation of Actinobacteria with other bacteria is known to lead to the production of compounds that are not produced in monoculture. Furthermore, the production of specific antibiotics is linked to the composition of the growth media that, in our co-culture conditions, exclusively consisted of the components of the prey living cells. Interestingly, our strategy led to the isolation of bacteria with interesting inhibitory activity against methicillin-resistant S. aureus (MRSA) as well as against Gram-negative bacteria.
| S-EPMC7168292 | biostudies-literature
Project description:We have discovered a new cluster of genes that is found exclusively in the Actinobacteria phylum. This locus includes genes for the 2-aminophenol meta-cleavage pathway and the shell proteins of a bacterial microcompartment (BMC) and has been named aromatics (ARO) for its putative role in the breakdown of aromatic compounds. In this study, we provide details about the distribution and composition of the ARO BMC locus and conduct phylogenetic, structural, and functional analyses of the first two enzymes in the catabolic pathway: a unique 2-aminophenol dioxygenase, which is exclusively found alongside BMC shell genes in Actinobacteria, and a semialdehyde dehydrogenase, which works downstream of the dioxygenase. Genomic analysis reveals variations in the complexity of the ARO loci across different orders. Some loci are simple, containing shell proteins and enzymes for the initial steps of the catabolic pathway, while others are extensive, encompassing all the necessary genes for the complete breakdown of 2-aminophenol into pyruvate and acetyl-CoA. Furthermore, our analysis uncovers two subtypes of ARO BMC that likely degrade either 2-aminophenol or catechol, depending on the presence of a pathway-specific gene within the ARO locus. The precise precursor of 2-aminophenol, which serves as the initial substrate and/or inducer for the ARO pathway, remains unknown, as our model organism Micromonospora rosaria cannot utilize 2-aminophenol as its sole energy source. However, using enzymatic assays, we demonstrate the dioxygenase's ability to cleave both 2-aminophenol and catechol in vitro, in collaboration with the aldehyde dehydrogenase, to facilitate the rapid conversion of these unstable and toxic intermediates. IMPORTANCE Bacterial microcompartments (BMCs) are proteinaceous organelles that are widespread among bacteria and provide a competitive advantage in specific environmental niches. Studies have shown that the genetic information necessary to form functional BMCs is encoded in loci that contain genes encoding shell proteins and the enzymatic core. This allows the bioinformatic discovery of BMCs with novel functions and expands our understanding of the metabolic diversity of BMCs. ARO loci, found only in Actinobacteria, contain genes encoding for phylogenetically remote shell proteins and homologs of the meta-cleavage degradation pathway enzymes that were shown to convert central aromatic intermediates into pyruvate and acetyl-CoA in gamma Proteobacteria. By analyzing the gene composition of ARO BMC loci and characterizing two core enzymes phylogenetically, structurally, and functionally, we provide an initial functional characterization of the ARO BMC, the most unusual BMC identified to date, distinctive among the repertoire of studied BMCs.
| S-EPMC10470539 | biostudies-literature