Biologically active secondary metabolites from myxobacteria

New chemical structures with proven biological activity still are badly needed for a host of applications and are intensively screened for. Suitable compounds may be used as such, or in the form of their derivatives or, equally important, may serve as lead compounds for designing synthetic analogs. One way to new compounds is the exploitation of new producer organisms. During the past 15 years the myxobacteria have been shown in our laboratories to be a rich source of novel secondary metabolites, many of the compounds showing interesting and sometimes unique mechanisms of action. About 50 basic structures and nearly 300 structural variants have been elucidated, and almost all of them turned out to be new compounds. Several myxobacterial substances may have a good chance of an application.     

Improvement of hairy root cultures and plants by changing biosynthetic pathways leading to pharmaceutical metabolites: Strategies and applications

A plethora of bioactive plant metabolites has been explored for pharmaceutical, food chemistry and agricultural applications. The chemical synthesis of these structures is often difficult, so plants are favorably used as producers. While whole plants can serve as a source for secondary metabolites and can be also improved by metabolic engineering, more often cell or organ cultures of relevant plant species are of interest. It should be noted that only in few cases the production for commercial application in such cultures has been achieved. Their genetic manipulation is sometimes faster and the production of a specific metabolite is more reliable, because of less environmental influences. In addition, upscaling in bioreactors is nowadays possible for many of these cultures, so some are already used in industry. There are approaches to alter the profile of metabolites not only by using plant genes, but also by using bacterial genes encoding modifying enzymes. Also, strategies to cope with unwanted or even toxic compounds are available. The need for metabolic engineering of plant secondary metabolite pathways is increasing with the rising demand for (novel) compounds with new bioactive properties. Here, we give some examples of recent developments for the metabolic engineering of plants and organ cultures, which can be used in the production of metabolites with interesting properties.     

Secondary transport as an efficient membrane transport mechanism for plant secondary metabolites

Plants produce a large number of secondary metabolites, such as alkaloids, terpenoids, and phenolic compounds. Secondary metabolites have various functions including protection against pathogens and UV light in plants, and have been used as natural medicines for humans utilizing their diverse biological activities. Many of these natural compounds are accumulated in a particular compartment such as vacuoles, and some are even translocated from source cells to sink organs via long distance transport. Both primary and secondary transporters are involved in such compartmentation and translocation, and many transporter genes, especially genes belonging to the multidrug and toxin extrusion type transporter family, which consists of 56 members in Arabidopsis, have been identified as responsible for the membrane transport of secondary metabolites. Better understandings of these transporters as well as the biosynthetic genes of secondary metabolites will be important for metabolic engineering aiming to increase the production of commercially valuable secondary metabolites in plant cells.     

Recent Updates on Corals from Nephtheidae

Marine natural products display a wide range of biological activities, which play a vital role in the innovation of lead compounds for the drug development. Soft corals have been ranked at the top in regard to the discovery of bioactive metabolites with potential pharmaceutical applications. Many of the isolated cembranoids revealed diverse biological activities, such as anticancer, antidiabetic and anti‐osteoporosis. Likewise, sterols from soft corals exhibited interesting biological potential as anti‐inflammatory, antituberculosis and anticancer. Consequently, investigating marine soft corals will definitely lead to the discovery of a large number of chemically varied secondary metabolites with countless bioactivities for possible applications in medicine and pharmaceutical industry. This review provides a complete survey of all metabolites isolated from the family Nephtheidae, from 2011 until November 2018, along with their natural sources and biological potential whenever possible.     

Bioactive secondary metabolites produced by microorganisms associated with plants

In the past few decades groups of scientists have focused their study on relatively new microorganisms called endophytes. By definition these microorganisms, mostly fungi and bacteria, colonise the intercellular spaces of the plant tissues. The mutual relationship between endophytic microorganisms and their host plants, taxanomy and ecology of endophytes are being studied. Some of these microorganisms produce bioactive secondary metabolites that may be involved in a host-endophyte relationship. Recently, many endophytic bioactive metabolites, known as well as new substances, possesing a wide variety of biological activities as antibiotic, antitumor, antiinflammatory, antioxidant, etc. have been identified. The microorganisms such as endophytes may be very interesting for biotechnological production of bioactive substances as medicinally important agents. Therefore the aim of this review is to briefly characterize endophytes and summarize the structuraly different bioactive secondary metabolites produced by endophytic microorganisms as well as microbial sources of these metabolites and their host plants.     

Applications of cyanobacteria in biotechnology

Cyanobacteria have gained a lot of attention in recent years because of their potential applications in biotechnology. We present an overview of the literature describing the uses of cyanobacteria in industry and services sectors and provide an outlook on the challenges and future prospects of the field of cyanobacterial biotechnology. Cyanobacteria have been identified as a rich source of biologically active compounds with antiviral, antibacterial, antifungal and anticancer activities. Several strains of cyanobacteria were found to accumulate polyhydroxyalkanoates, which can be used as a substitute for nonbiodegradable petrochemical-based plastics. Recent studies showed that oil-polluted sites are rich in cyanobacterial consortia capable of degrading oil components. Cyanobacteria within these consortia facilitated the degradation processes by providing the associated oil-degrading bacteria with the necessary oxygen, organics and fixed nitrogen. Cyanobacterial hydrogen has been considered as a very promising source of alternative energy, and has now been made commercially available. In addition to these applications, cyanobacteria are also used in aquaculture, wastewater treatment, food, fertilizers, production of secondary metabolites including exopolysaccharides, vitamins, toxins, enzymes and pharmaceuticals. Future research should focus on isolating new cyanobacterial strains producing high value products and genetically modifying existing strains to ensure maximum production of the desired products. Metagenomic libraries should be constructed to discover new functional genes that are involved in the biosynthesis of biotechnological relevant compounds. Large-scale industrial production of the cyanobacterial products requires optimization of incubation conditions and fermenter designs in order to increase productivity.     

Bioactive natural products from marine cyanobacteria for drug discovery

The prokaryotic marine cyanobacteria continue to be an important source of structurally bioactive secondary metabolites. A majority of these molecules are nitrogen-containing compounds biosynthesized by large multimodular nonribosomal polypeptide (NRP) or mixed polyketide-NRP enzymatic systems. A total of 128 marine cyanobacterial alkaloids, published in the literature between January 2001 and December 2006, are presented in this review with emphasis on their biosynthesis and biological activities. In addition, a number of highly cytotoxic compounds such as hectochlorin, lyngbyabellins, apratoxins, and aurilides have been identified as potential lead compounds for the development of anticancer agents. A brief coverage on the distribution of natural product biosynthetic genes as well as the mechanisms of tailoring enzymes involved in the biosynthesis of cyanobacterial compounds will also be given.     

Ecological and biotechnological importance of secondary metabolites produced by coral-associated bacteria

Symbiotic relationships between corals and their associated micro-organisms are essential to maintain host homeostasis. Coral-associated bacteria (CAB) can have different beneficial roles in the coral metaorganism, such as metabolizing essential nutrients for the coral host and protecting the coral from pathogens. Many CAB exert these functions via secondary metabolites, which include antibacterial, antifouling, antitumour, antiparasitic and antiviral compounds. This review describes how analysis of CAB has led to the discovery of secondary metabolites with potential biotechnological applications. The most commonly found types of secondary metabolites, antimicrobial and antibiofilm compounds, are emphasized and described. Recently developed methods that can be applied to enhance the culturing of CAB from shallow-water reefs and the less-studied deep-sea coral reefs are also discussed. Last, we suggest how the combined use of meta-omics and innovative growth-diffusion techniques can vastly improve the discovery of novel compounds in coral environments.     

Biological activities and potential cosmeceutical applications of bioactive components from brown seaweeds: a review

Seaweeds are the primary producers of all aquatic ecosystems. Chemical constituents isolated from diverse classes of seaweeds exert a wide range of nutritional, functional and biological activities. Unique metabolites of seaweeds possess specific biological properties that make them potential ingredients of many industrial applications such as functional foods, pharmaceuticals and cosmeceuticals. Cosmeceuticals of natural origin are becoming more popular than synthetic cosmetics. Hence, the investigation of new seaweeds derived functional components, a different source of natural products, has proven to be a promising area of cosmeceutical studies. Brown seaweeds also produce a range of active components including unique secondary metabolites such as phlorotannins and many of which have specific biological activities that give possibilities for their economic utilization. Brown seaweeds derived active compounds have been shown various functional properties including, antioxidant, antiwrinkling, whitening, antiinflammatory and antiallergy. It is well-known that these kind of biological effects are closely associated with cosmeceutical preparations. This communication reviews the current knowledge on brown seaweeds derived metabolites with various biological activities and the potential use as cosmeceutical ingredients. It is hoped that the reviewed literature on multifunctional properties of brown seaweeds will improve access to the seaweed based natural products specially the ability to incorporate these functional properties in cosmeceutical applications.     

Saccharopolyspora: an underexplored source for bioactive natural products

Actinomycetes are a rich source for secondary metabolites with a diverse array of biological activities. Among the various genera of actinomycetes, the genus Saccharopolyspora has long been recognized as a potential source for antibiotics and other therapeutic leads that belong to diverse classes of natural products. Members of the genus Saccharopolyspora have been widely reported from several natural sources including both terrestrial and marine environments. A plethora of this genus has been chemically investigated for the production of novel natural products with interesting pharmacological effects. Therefore, Saccharopolyspora is considered one of the pharmaceutical important genera that could provide further chemical diversity with potential lead compounds. In this review, the literature from 1976 until December 2018 was covered, providing a comprehensive survey of all natural products derived from this genus and their semi-synthetic derivatives along with their biological activities, whenever applicable. Moreover, the biological diversity of Saccharopolyspora species and their habitats were also discussed.     

Endophytic fungi: novel sources of anticancer lead molecules

Cancer is a major killer disease all over the world and more than six million new cases are reported every year. Nature is an attractive source of new therapeutic compounds, as a tremendous chemical diversity is found in millions of species of plants, animals, and microorganisms. Plant-derived compounds have played an important role in the development of several clinically useful anti-cancer agents. These include vinblastine, vincristine, camptothecin, podophyllotoxin, and taxol. Production of a plant-based natural drug is always not up to the desired level. It is produced at a specific developmental stage or under specific environmental condition, stress, or nutrient availability; the plants may be very slow growing taking several years to attain a suitable growth phase for product accumulation and extraction. Considering the limitations associated with the productivity and vulnerability of plant species as sources of novel metabolites, microorganisms serve as the ultimate, readily renewable, and inexhaustible source of novel structures bearing pharmaceutical potential. Endophytes, the microorganisms that reside in the tissues of living plants, are relatively unstudied and offer potential sources of novel natural products for exploitation in medicine, agriculture and the pharmaceutical industry. They develop special mechanisms to penetrate inside the host tissue, residing in mutualistic association and their biotransformation abilities opens a new platform for synthesis of novel secondary metabolites. They produce metabolites to compete with the epiphytes and also with the plant pathogens to maintain a critical balance between fungal virulence and plant defense. It is therefore necessary that the relationship between the plants and endophytes during the accumulation of these secondary metabolites is studied. Insights from such research would provide alternative methods of natural product drug discovery which could be reliable, economical, and environmentally safe.     

Anthraquinone profile,antioxidant and enzyme inhibitory effect of root extracts of eight Asphodeline taxa from Turkey: can Asphodeline roots be considered as a new source of natural compounds?

Plant-based foods have become attractive for scientists and food producers. Beneficial effects related to their consumption as dietary supplements are due to the presence of natural occurring secondary metabolites. In this context, studies on these products are important for natural and safely food ingredients evaluation. The aim of this study was to evaluate root extract of eight Asphodeline species as antioxidants, enzyme inhibitors and phytochemical content. Spectrophotometric antioxidant and enzyme inhibitory assays were performed. Total phenolic and flavonoids contents as well as the chemical free-anthraquinones profiles were determined using routinely procedure (HPLC-PDA). Data show that Asphodeline roots can be considered as a new source of natural compounds and can be used as a valuable dietary supplement. Some differences related to biological activities can be inferred to other phytochemicals that can be considered in the future for their synergic or competitive activities.     

Biophysical and biochemical characterization of active secondary metabolites from Aspergillus allahabadii

Fungal secondary metabolites are a diverse group of natural chemical products with physiological relevance. We aimed to identify bioactive secondary metabolites from Aspergillus allahabadii. We used “activity-guided fractionation” strategy for the isolation of secondary metabolites. Crude extracts showed good antibacterial activity. Two antibacterial secondary metabolites have been isolated from the crude extract. Chemical characterization of these compounds was performed using biophysical techniques (FT-IR, NMR, and mass spectrometry). Structural characterization confirmed these to be pyrone derivatives: 3-hydroxy 2-methyl 4-pyrone and 5-hydroxy-2-(hydroxymethyl)-4H-pyrone. These bioactive pyrone derivatives have been identified as maltol and kojic acid. From our initial observations, we infer that these pyrone derivatives have potent antimicrobial, antioxidant, antidiabetic, and mosquito larvicidal activities and no cytotoxicity. These compounds could have potential therapeutic and biomedical applications, but further mechanistic studies using animal models are very much necessary.     

Healthy and unhealthy plants: The effect of stress on the metabolism of Brassicaceae

Brassicaceae plants are one of the most popular vegetables consumed all over the world and considered to be a good source of bioactive phytochemicals. Additionally, Brassica species and varieties are increasingly becoming a research model in plant science, as a consequence of the importance of their primary and secondary metabolites. Plant interaction with environmental stress factors including animals and insects herbivory, pathogens, metal ions, light, among others, is known to lead to the activation of various defense mechanisms resulting in a qualitative and/or quantitative change in plant metabolite production. Pre-harvest and/or post-harvest conditions are also known to affect this, since plants produce signaling molecules (e.g. salicylic acid, jasmonic acid, etc.) that cause a direct or indirect activation of metabolic pathways. That ultimately affects the production of phytochemicals, such as carbohydrates (sucrose and glucose), amino acids, phenolics (phenylpropanoids and flavonoids) and glucosinolates. These phytochemicals have diverse applications due to their antimicrobial, antioxidant and anti-carcinogenic properties, but on the other hand these compounds or their breakdown products can act as anti-nutritional factors in diet. In this review we report a wide range of the stress-induced metabolic responses in the Brassica plants commonly used for human consumption.     

Drugs from the seas - current status and microbiological implications

The oceans are the source of a large group of structurally unique natural products that are mainly accumulated in invertebrates such as sponges, tunicates, bryozoans, and molluscs. Several of these compounds (especially the tunicate metabolite ET-743) show pronounced pharmacological activities and are interesting candidates for new drugs primarily in the area of cancer treatment. Other compounds are currently being developed as an analgesic (ziconotide from the mollusc Conus magus) or to treat inflammation. Numerous natural products from marine invertebrates show striking structural similarities to known metabolites of microbial origin, suggesting that microorganisms (bacteria, microalgae) are at least involved in their biosynthesis or are in fact the true sources of these respective metabolites. This assumption is corroborated by several studies on natural products from sponges that proved these compounds to be localized in symbiotic bacteria or cyanobacteria. Recently, molecular methods have successfully been applied to study the microbial diversity in marine sponges and to gain evidence for an involvement of bacteria in the biosynthesis of the bryostatins in the bryozoan Bugula neritina.     

Natural products potential of Dictyoceratida sponges-associated micro-organisms

The marine environment represents one of the most underexplored environments in the world. Marine sponges have a higher taxonomic diversity according to definite environmental conditions. They have been considered interesting sources for bioactive compounds. Dictyoceratida sponges are divided into five families which are widely distributed and habituating different types of micro-organisms. However, some secondary metabolites are probably not produced by the sponges themselves, but rather by their associated micro-organisms. These secondary metabolites are characterized by different chemical structures and consequently different biological activities. This review outlines the reported secondary metabolites from micro-organisms associated with Dictyoceratida sponges and their investigated biological activities from 1991 to 2019. The increasing research studies in this field can play a major role in marine microbial natural products drug discovery in the future.     

Complex Marine Natural Products as Potential Epigenetic and Production Regulators of Antibiotics from a Marine Pseudomonas aeruginosa

Marine microbes are capable of producing secondary metabolites for defense and competition. Factors exerting an impact on secondary metabolite production of microbial communities included bioactive natural products and co-culturing. These external influences may have practical applications such as increased yields or the generation of new metabolites from otherwise silent genes in addition to reducing or limiting the production of undesirable metabolites. In this paper, we discuss the metabolic profiles of a marine Pseudomonas aeruginosa in the presence of a number of potential chemical epigenetic regulators, adjusting carbon sources and co-culturing with other microbes to induce a competitive response. As a result of these stressors certain groups of antibiotics or antimalarial agents were increased most notably when treating P. aeruginosa with sceptrin and co-culturing with another Pseudomonas sp. An interesting cross-talking event between these two Pseudomonas species when cultured together and exposed to sceptrin was observed.     

De novo biosynthesis of garbanzol and fustin in Streptomyces albus based on a potential flavanone 3-hydroxylase with 2-hydroxylase side activity

Flavonoids are important plant secondary metabolites, which were shown to have antioxidant, anti-inflammatory or antiviral activities. Heterologous production of flavonoids in engineered microbial cell factories is an interesting alternative to their purification from plant material representing the natural source. The use of engineered bacteria allows to produce specific compounds, independent of soil, climatic or other plant-associated production parameters. The initial objective of this study was to achieve an engineered production of two interesting flavanonols, garbanzol and fustin, using Streptomyces albus as the production host. Unexpectedly, the engineered strain produced several flavones and flavonols in the absence of the additional expression of a flavone synthase (FNS) or flavonol synthase (FLS) gene. It turned out that the heterologous flavanone 3-hydroxylase (F3H) has a 2-hydroxylase side activity, which explains the observed production of 7,4′-dihydroxyflavone, resokaempferol, kaempferol and apigenin, as well as the biosynthesis of the extremely rare 2-hydroxylated intermediates 2-hydroxyliquiritigenin, 2-hydroxynaringenin and probably licodione. Other related metabolites, such as quercetin, dihydroquercetin and eriodictyol, have also been detected in culture extracts of this recombinant strain. Hence, the enzymatic versatility of S. albus can be conveniently exploited for the heterologous production of a large diversity of plant metabolites of the flavonoid family.     

Chemical composition of essential oils from leaves of Helicteres guazumifolia (Sterculiaceae), Piper tuberculatum (Piperaceae), Scoparia dulcis (Arecaceae) and Solanum subinerme (Solanaceae) from Sucre, Venezuela

Essential oils, biosynthesized and accumulated in aromatic plants, have a wide range of applications in the pharmaceutical health, cosmetics, food and agricultural industry. This study aimed to analyze the secondary metabolites in some plant species in order to contribute to their chemotaxonomy. Leaves from Helicteres guazumifolia, Piper tuberculatum, Scoparia dulcis and Solanum subinerme were collected and their essential oils were obtained by means of hydro-distillation. The oil fraction was analyzed and identified by GC/MS. The extraction yields were of 0.004, 0.032, 0.016 and 0.005%, and the oil constituents of 88.00, 89.80, 87.50 and 89.47%, respectively. The principal oils found were: non-terpenoids volatile secondary metabolites (30.28%) in H. guazumifolia; sesquiterpenoids (20.82 and 26.09%) and oxigen derivated (52.19 and 25.18%) in P. tuberculatum and S. dulcis; and oxigen diterpenoids (39.67%) in S. subinerme. The diisobuthylphtalate (13.11%) in H. guazumifolia, (-)-spathulenol (11.37%) in P. tuberculatum and trans-phytol (8.29 and 36.00%) in S. dulcis and S. subinerme, were the principal constituents in their respective essential oils. The diisooctylphtalate were the essential oil common to all species, but the volatile compounds such as trans-pinane, L-linalool, beta-ionone, isophytol, neophytadiene, trans-phytol, dibutylphtalate and methyl hexadecanoate, were only detected in three of these essences. This suggests that these plants may require similar secondary metabolites for their ecological interactions, possibly due to common environmental factors.     

Comments on coral reef regeneration, bioerosion, biogeography, and chemical ecology: future directions

This paper represents a brief review of three processes operating on coral reefs and the results of studies of a fourth process, and how those results may be applied to the benefit of humankind. The areas are reef regeneration processes; bioerosion; dispersal, recruitment and biogeography of corals; and chemical ecology and natural products chemistry of reef organisms. Possible future directions for research will also be considered in each area. Regarding reef regeneration processes, coral reefs are degrading rapidly on a global scale due to over-fishing, fishing techniques causing habitat destruction, deforestation, mass mortalities of key reef species, nutrient enrichment and sedimentation. Seeding of reefs with the larvae of corals and other key reef organisms, such as echinoids, may help to promote and enhance reef regeneration in the future. Such techniques will be made possible by studies of the embryology, larval ecology, dispersal and recruitment processes, and related local physical oceanographic processes. Regarding bioerosion, both internal and external bioerosion are affected by grazers and predators. Bioerosion is also affected by nutrient enrichment, as shown through correlative studies (Great Barrier Reef) and studies of opportunity (Kaneohe Bay). Ongoing experiments such as ENCORE will help to answer questions about the role of dissolved nutrients in enhancing internal bioerosion. Questions still remain, however, regarding the role of particulates in promoting internal bioerosion and the resultant weakening of and negative growth in the reef framework. Regarding dispersal, recruitment and the biogeography of corals, it is now known that most species of coral reproduce via broadcasting, although there appear to be proportionally more brooders in the Caribbean than in the western Pacific. Differential extinctions in the western Pacific vs. the western Atlantic have contributed to the biogeographic distribution of corals we observe today and the concentric isoclines of species diversity in numerous reef organisms in the western Pacific. The role of reproductive mode in contributing to these patterns is, however, still not understood. Investigations into the roles of different larval longevities and reproductive modes may help us answer questions regarding their differential distribution and the potential effects of major perturbations such as global warming on future distributions. With respect to the chemical ecology of alcyonacean octocorals (soft corals), four functions have been determined thus far for secondary metabolites in this group, anti-predation, anti-competition (allelopathy), anti-fouling, and enhancement of reproductive success. Investigations of alcyonacean reproduction has revealed that it may be necessary for several secondary metabolites to be present simultaneously before a function may be realized or fully manifested. This raises questions regarding the manner in which novel compounds are tested by medical laboratories for bioactivity using a single compound. Simultaneously testing of multiple compounds derived from a single organism may be necessary in the future to reveal potential valuable synergistic bioactivity. Also, some novel secondary metabolites may have other valuable commercial applications, as is the case with the UV-absorbing compounds of corals and other reef organisms found on the Great Barrier Reef. In order to avoid overlooking medically or commercially valuable functions of these compounds, broader testing may be necessary.