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Heterologous biosynthesis of tetrahydrocannabinolic acid (THCA) in yeast is a biotechnological process in Natural Product Biotechnology that was recently introduced. Based on heterologous genes from Cannabis sativa and Streptomyces spp. cloned into Saccharomyces cerevisiae, the heterologous biosynthesis was fully embedded as a proof of concept. Low titer and insufficient biocatalytic rate of most enzymes require systematic optimization of recombinant catalyst by protein engineering and consequent C-flux improvement of the yeast chassis for sufficient precursor (acetyl-CoA), energy (ATP), and NADH delivery. In this review basic principles of in silico analysis of anabolic pathways towards olivetolic acid (OA) and cannabigerolic acid (CBGA) are elucidated and discussed to identify metabolic bottlenecks. Based on own experimental results, yeasts are discussed as potential platform organisms to be introduced as potential cannabinoid biofactories. Especially feeding strategies and limitations in the committed mevalonate and olivetolic acid pathways are in focus of in silico and experimental studies to validate the scientific and commercial potential as a realistic alternative to the plant Cannabis sativa. Key points • First time critical review of the heterologous process for recombinant THCA/CBDA production and critical review of bottlenecks and limitations for a bioengineered technical process • Integrative approach of protein engineering, systems biotechnology, and biochemistry of yeast physiology and biosynthetic cannabinoid enzymes • Comparison of NphB and CsPT aromatic prenyltransferases as rate-limiting catalytic steps towards cannabinoids in yeast as platform organisms [ABSTRACT FROM AUTHOR]

Abstract The struggle of humans versus pathogens is a never ending battle. Since the discovery of antibiotics humans have tipped the scales in their favour, but today bacteria are nullifying this advantage by developing resistance mechanisms against these molecules. The plethora of different antibiotics active against pathogens is shrinking while the discovery of new molecules is arduous. Especially the development of drugs active against Gram− pathogens continues slowly. New strategies to discover novel, potent antibiotics are hence needed. Adopting the optimistic view of technological singularity, innovative and disruptive approaches are required and hence proposed to lift the current conundrum. In this review, questions are answered on where and how to look for new natural product hit molecules with antibacterial activity, on how the field of synthetic biology can aid the contemporary pharmaceutical challenge and whether we are ready to make the transition towards other approaches, such as narrow-spectrum antibiotics and phage therapy. [ABSTRACT FROM AUTHOR]

A practical and efficient four-step synthesis of the natural product deca-4,6,8-triyn-1-ol has been achieved beginning with (triisopropylsilyl)acetylene. This trialkyne has potential utility as a key intermediate for the total synthesis of the antitumor butenolide natural product vernoniyne. [ABSTRACT FROM AUTHOR]

Utilization of biocatalysts with high accessibility and availability, which have recently been applied in the preparation of enantiomerically enriched starting materials and synthetic intermediates for natural product syntheses (mainly 2013–2017) are summarized in this review. The main contents are as follows: 1) recruitment of biocatalysts for the transformation of organic compounds; 2) special precautions for preparative-scale biocatalytic synthetic experiments; 3) asymmetric reduction of carbonyl substrates; 4) kinetic resolution of alcohol and carboxylate enantiomers; 5) desymmetrization of multifunctional alcohol and carboxylate substrates; and 6) recognition of remote and non-central chirality. [ABSTRACT FROM AUTHOR]

While bread is a staple food in western culture, it is a supplementary food in rice eating societies. The objective of this study was to investigate the effect of extrinsic flour information on bread acceptability in one of rice eating societies, Korea. Consumers evaluated six bread samples either blind or with flour information including which country it was produced and whether organic production was applied or not. Consumers' interest in health or in natural products was also measured. The results showed that information of using domestic flour had a strong positive effect on overall bread acceptability, while organic information particularly affected flavor preferences. Health or natural product interested people showed more distinct tendency of the above origin and organic effect. Texture liking remained unaffected by extrinsic information in all cases. Practical applications The results implied the possibility of consumers who consider bread as supplementary food may be either lacking in knowledge about bread quality in relation to flours, resulting in biased expectation induced from extrinsic information or may not care bread quality as carefully as consumers in societies who consume bread as staple food. Consumer attitudes to health and to natural product were observed to be important considerations when developing market strategies for bread consumers in Korea. [ABSTRACT FROM AUTHOR]

Worldwide breast cancer is the most common cancer in women. For many years clinicians and the researchers are examining and exploring various therapeutic modalities for breast cancer. Yet the disease has remained unconquered and the quest for cure is still going on. Present-day strategy of breast cancer therapy and prevention is either combination of a number of drugs or a drug that modulates multiple targets. In this regard natural products are now becoming significant options. Curcumin exemplifies a promising natural anticancer agent for this purpose. This review primarily underscores the modulatory effect of curcumin on the cancer hallmarks. The focus is its anticancer effect in the complex pathways of breast carcinogenesis. Curcumin modulates breast carcinogenesis through its effect on cell cycle and proliferation, apoptosis, senescence, cancer spread and angiogenesis. Largely the NFkB, PI3K/Akt/mTOR, MAPK and JAK/STAT are the key signaling pathways involved. The review also highlights the curcumin mediated modulation of tumor microenvironment, cancer immunity, breast cancer stem cells and cancer related miRNAs. Using curcumin as a therapeutic and preventive agent in breast cancer is perplexed by its diverse biological activity, much of which remains inexplicable. The information reviewed here should point toward potential scope of future curcumin research in breast cancer. [ABSTRACT FROM AUTHOR]

Actinomycetes are a major source of bioactive natural products with important pharmaceutical properties. Understanding the natural enzymatic assembly of complex small molecules is important for rational metabolic pathway design to produce “artificial” natural products in bacterial cells. This review will highlight current research on the biosynthetic mechanisms of two classes of nitrogen-containing natural products, C7N aminocyclitols and bis-indoles. Validamycin A is a member of C7N aminocyclitol natural products fromStreptomyces hygroscopicus. Here, two important biosynthetic steps, pseudoglycosyltranferase-catalyzed C–N bond formation, and C7-sugar phosphate cyclase-catalyzed divergent carbasugar formation, will be reviewed. In addition, the bis-indolic natural products indolocarbazole, staurosporine fromStreptomycessp. TP-A0274, and rearranged bis-indole violacein fromChromobacterium violaceumare reviewed including the oxidative course of the assembly pathway for the bis-indolic scaffold. The identified biosynthesis mechanisms will be useful to generating new biocatalytic tools and bioactive compounds. Biosynthesis of C7N aminocyclitols and bis-indoles. [ABSTRACT FROM AUTHOR]

Complementary and alternative medicine (CAM) is widely used for menopause, although not all women disclose use to their healthcare providers. This narrative review aims to expand providers' understanding of cross-cultural approaches to treating and managing menopause by providing an overarching framework and perspective on CAM treatments. Increased provider understanding and awareness may improve not only provider-patient communication but also effectiveness of treatments. The distinction between illness (what patients suffer) and disease (what physicians treat) highlights the gap between what patients seek and doctors provide, and may help clarify why many women seek CAM at menopause. For example, CAM is often sought by women for whom biomedicine has been unsuccessful or inaccessible. We review the relevance to menopause of three CAM categories: natural products, mind-body practices including meditation, and other complementary health approaches including traditional Chinese medicine (TCM) and Japanese Kampo. Assessing the effectiveness of CAM is challenging because of the individualized nature of illness patterns and associated treatments, which complicate the design of randomized controlled trials. Because many women seek CAM due to inefficacy of biomedical treatments, or cultural or economic marginalization, biomedical practitioners who make an effort to learn about CAM and ask patients about their CAM use or interest may dramatically improve the patient-provider relationship and rapport, as well as harnessing the 'meaning response' (Moerman, 2002) imbued in the clinical encounter. By working with women to integrate their CAM-related health-seeking behaviors and treatments, providers may also boost the efficacy of their own biomedical treatments. [ABSTRACT FROM AUTHOR]

Macrocycles are appealing drug candidates due to their high affinity, specificity, and favorable pharmacological properties. In this study, we explored the effects of chemical modifications to a natural product macrocycle upon its activity, 3D geometry, and conformational entropy. We chose thiocillin as a model system, a thiopeptide in the ribosomally encoded family of natural products that exhibits potent antimicrobial effects against Gram-positive bacteria. Since thiocillin is derived from a genetically encoded peptide scaffold, site-directed mutagenesis allows for rapid generation of analogues. To understand thiocillin's structure-activity relationship, we generated a site-saturation mutagenesis library covering each position along thiocillin's macrocyclic ring. We report the identification of eight unique compounds more potent than wild-type thiocillin, the best having an 8-fold improvement in potency. Computational modeling of thiocillin's macrocyclic structure revealed a striking requirement for a low-entropy macrocycle for activity. The populated ensembles of the active mutants showed a rigid structure with few adoptable conformations while inactive mutants showed a more flexible macrocycle which is unfavorable for binding. This finding highlights the importance of macrocyclization in combination with rigidifying post-translational modifications to achieve high-potency binding. [ABSTRACT FROM AUTHOR]

The development of personal care formulations incorporates the deliberation of the prerequisite product rheology and the right rheology modifier to deliver these effects. While the effectiveness of the finished product will hinge on the selection and level of active ingredients and excipients, the esthetics and even the penetration of these actives into the stratum corneum will be affected by the product rheology. Rheology modifiers are frequently denoted as thickeners, and while increasing the apparent viscosity should enhance the perception of quality in a formulation, this is only one aspect of rheological control. The product itself can be Newtonian or pseudoplastic, thixotropic, existing as a ringing gel or a stringy flowable liquid. This changes the way that the product appears in the bottle, the ease with which aliquots are poured or scooped from the packaging, the process of rubbing it into the skin or along the hair shaft, and upon using, the rinsing and removal of the product. It will also be vital to select the correct rheological characteristics to guarantee the stability of the finished formulation. By changing the structure of polymeric rheology modifiers, the impact on the sensorial properties and performance characteristics can be investigated. Careful selection of monomers, structure and other co-ingredients will result in products optimized for use in skin care formulations. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Starting with the discovery of streptomycin, the promise of natural products research on actinomycetes has been captivating researchers and offered an array of lifesaving antibiotics. However, most of the actinomycetes have received a little attention of researchers beyond isolation and activity screening. Noticeable gaps in genomic information and associated biosynthetic potential of actinomycetes are mainly the reasons for this situation, which has led to a decline in the discovery rate of novel antibiotics. Recent insights gained from genome mining have revealed a massive existence of previously unrecognized biosynthetic potential in actinomycetes. Successive developments in next-generation sequencing, genome editing, analytical separation and high-resolution spectroscopic methods have reinvigorated interest on such actinomycetes and opened new avenues for the discovery of natural and naturalinspired antibiotics. This article describes the new dimensions that have driven the ongoing resurgence of research on actinomycetes with historical background since the commencement in 1940, for the attention of worldwide researchers. Coupled with increasing advancement in molecular and analytical tools and techniques, the discovery of next-generation antibiotics could be possible by revisiting the untapped potential of actinomycetes from different natural sources. [ABSTRACT FROM AUTHOR]

The green and efficient preparation of natural products from biomass is considered an important area of interest in pharmaceutical applications. In this study, we aimed to provide a practical example with a popular traditional Chinese medicine, Anemarrhenae Rhizome, and showcase the orthogonal use of column chromatography with polyamide and macroporous adsorption resins to selectively concentrate and efficiently purify four bioactive compounds: neomangiferin (NMF), mangiferin (MF), timosaponin B-II (TS B-II), and timosaponin A-III (TS A-III). First, polyamide T60-100 was employed to fractionalize the crude extracts of Anemarrhenae Rhizome. Macroporous resin HPD400 was subsequently used to purify the xanthones and steroidal saponins. Under the optimized conditions, 2.31 g of NMF, 4.10 g of MF, 12.87 g of TS B-II, and 2.78 g of TS A-III were prepared from 1 kg of crude materials, and their purities were 90.0, 92.15, 90.8, and 92.61%, respectively. The results of this study indicate that the combined column chromatography with polyamide and macroporous adsorption resins can be referenced as a green and efficient alternative for large-scale purification of bioactive ingredients from herbal raw materials. [ABSTRACT FROM AUTHOR]

A synthetic approach to diverse scaffolds was developed that was inspired by diterpene biosynthesis. Initial scaffolds, generated using Diels–Alder reactions of furyl-functionalised amines, were transformed into alternative scaffolds using cleavage, ring expansion, annulation and rearrangement reactions. In total, 25 diverse scaffolds were prepared that were shown to have high natural product-likeness. [ABSTRACT FROM AUTHOR]

A table of contents for volume 33, number 8, August 2016 issue of the periodical "Natural Products Reports" is presented.

Covering: 2003 to 2016 The last decade has seen the first major discoveries regarding the genomic basis of plant natural product biosynthetic pathways. Four key computationally driven strategies have been developed to identify such pathways, which make use of physical clustering, co-expression, evolutionary co-occurrence and epigenomic co-regulation of the genes involved in producing a plant natural product. Here, we discuss how these approaches can be used for the discovery of plant biosynthetic pathways encoded by both chromosomally clustered and non-clustered genes. Additionally, we will discuss opportunities to prioritize plant gene clusters for experimental characterization, and end with a forward-looking perspective on how synthetic biology technologies will allow effective functional reconstitution of candidate pathways using a variety of genetic systems. [ABSTRACT FROM AUTHOR]

Covering: 2006 to 2016 The computational mining of genomes has become an important part in the discovery of novel natural products as drug leads. Thousands of bacterial genome sequences are publically available these days containing an even larger number and diversity of secondary metabolite gene clusters that await linkage to their encoded natural products. With the development of high-throughput sequencing methods and the wealth of DNA data available, a variety of genome mining methods and tools have been developed to guide discovery and characterisation of these compounds. This article reviews the development of these computational approaches during the last decade and shows how the revolution of next generation sequencing methods has led to an evolution of various genome mining approaches, techniques and tools. After a short introduction and brief overview of important milestones, this article will focus on the different approaches of mining genomes for secondary metabolites, from detecting biosynthetic genes to resistance based methods and “evo-mining” strategies including a short evaluation of the impact of the development of genome mining methods and tools on the field of natural products and microbial ecology. [ABSTRACT FROM AUTHOR]

Covering: up to 2016 In this highlight, we describe the current landscape for dereplication and discovery of natural products based on the measurement of the intact mass by LC-MS. Often it is assumed that because better mass accuracy (provided by higher resolution mass spectrometers) is necessary for absolute chemical formula determination (≤1 part-per-million), that it is also necessary for dereplication of natural products. However, the average ability to dereplicate tapers off at ∼10 ppm, with modest improvement gained from better mass accuracy when querying focused databases of natural products. We also highlight some recent examples of how these platforms are applied to synthetic biology, and recent methods for dereplication and correlation of substructures using tandem MS data. We also offer this highlight to serve as a brief primer for those entering the field of mass spectrometry-based natural products discovery. [ABSTRACT FROM AUTHOR]

Standardization is one of the foundational features of modern-day engineering, and the use of standardized parts and processes is a key element that distinguishes bona fide synthetic biology from traditional genetic engineering. Here, we discuss the role of standardization in natural product synthetic biology, focusing on standardization of data on biosynthetic pathways and gene clusters, as well as the role of standardization in the process of biosynthetic gene cluster engineering. [ABSTRACT FROM AUTHOR]

Covers the period up to 2016 Bacterial-based natural products have long represented a promising resource for the development of commercially relevant therapeutics, and more than two thirds of these products have been developed from members of the genus Streptomyces. The extensive sequencing of bacterial genomes suggests that the majority of gene clusters encoding natural products are silent and not expressed under standard laboratory conditions. However, these clusters can be activated through systematic exchanges between native transcriptionally silent promoters and transcriptionally active promoters. Therefore, the availability of well-studied constitutive and inducible promoters is of the utmost importance for identifying natural products encoded by silent gene clusters. This manuscript provides an overview of the promoter control elements for streptomycetes and examples of their successful application in refactoring the biosynthetic pathways of natural products. [ABSTRACT FROM AUTHOR]

Covering: 2012 to 2016 Metabolic engineering using systems biology tools is increasingly applied to overproduce secondary metabolites for their potential industrial production. In this Highlight, recent relevant metabolic engineering studies are analyzed with emphasis on host selection and engineering approaches for the optimal production of various prokaryotic secondary metabolites: native versus heterologous hosts (e.g., Escherichia coli) and rational versus random approaches. This comparative analysis is followed by discussions on systems biology tools deployed in optimizing the production of secondary metabolites. The potential contributions of additional systems biology tools are also discussed in the context of current challenges encountered during optimization of secondary metabolite production. [ABSTRACT FROM AUTHOR]

Covering: 2000 to 2016 Progress in synthetic biology is enabled by powerful bioinformatics tools allowing the integration of the design, build and test stages of the biological engineering cycle. In this review we illustrate how this integration can be achieved, with a particular focus on natural products discovery and production. Bioinformatics tools for the DESIGN and BUILD stages include tools for the selection, synthesis, assembly and optimization of parts (enzymes and regulatory elements), devices (pathways) and systems (chassis). TEST tools include those for screening, identification and quantification of metabolites for rapid prototyping. The main advantages and limitations of these tools as well as their interoperability capabilities are highlighted. [ABSTRACT FROM AUTHOR]

Covering up to end 2015 Microbial fermentation provides an attractive alternative to chemical synthesis for the production of structurally complex natural products. In most cases, however, production titers are low and need to be improved for compound characterization and/or commercial production. Owing to advances in functional genomics and genetic engineering technologies, microbial hosts can be engineered to overproduce a desired natural product, greatly accelerating the traditionally time-consuming strain improvement process. This review covers recent developments and challenges in the engineering of native and heterologous microbial hosts for the production of bacterial natural products, focusing on the genetic tools and strategies for strain improvement. Special emphasis is placed on bioactive secondary metabolites from actinomycetes. The considerations for the choice of host systems will also be discussed in this review. [ABSTRACT FROM AUTHOR]

Catalysts are a vital part of synthetic chemistry. However, there are still many important reactions for which catalysts have not been developed. The use of enzymes as biocatalysts for synthetic chemistry is growing in importance due to the drive towards sustainable methods for producing both bulk chemicals and high value compounds such as pharmaceuticals, and due to the ability of enzymes to catalyse chemical reactions with excellent stereoselectivity and regioselectivity. Such challenging transformations are a common feature of natural product biosynthetic pathways. In this mini-review, we discuss the potential to use biosynthetic pathways as a starting point for biocatalyst discovery. We introduce the reader to natural product assembly and tailoring, then focus on four classes of enzyme that catalyse C H bond activation reactions to functionalize biosynthetic precursors. Finally, we briefly discuss the challenges involved in novel enzyme discovery. [ABSTRACT FROM AUTHOR]

The article discusses the synthesis of functionalized y-lactams. Topics addressed include the methodologies of synthesis and synthesis of some natural products. Also discussed are intermolecular microwave-facilitated cyclization reaction, zinc-promoted Aza-Barbier reaction and sugars used as chiral pool for y-lactams.

Microorganisms produce a wide range of natural products (NPs) with clinically and agriculturally relevant biological activities. In bacteria and fungi, genes encoding successive steps in a biosynthetic pathway tend to be clustered on the chromosome as biosynthetic gene clusters (BGCs). Historically, “activity-guided” approaches to NP discovery have focused on bioactivity screening of NPs produced by culturable microbes. In contrast, recent “genome mining” approaches first identify candidate BGCs, express these biosynthetic genes using synthetic biology methods, and finally test for the production of NPs. Fungal genome mining efforts and the exploration of novel sequence and NP space are limited, however, by the lack of a comprehensive catalog of BGCs encoding experimentally-validated products. In this study, we generated a comprehensive reference set of fungal NPs whose biosynthetic gene clusters are described in the published literature. To generate this dataset, we first identified NCBI records that included both a peer-reviewed article and an associated nucleotide record. We filtered these records by text and homology criteria to identify putative NP-related articles and BGCs. Next, we manually curated the resulting articles, chemical structures, and protein sequences. The resulting catalog contains 197 unique NP compounds covering several major classes of fungal NPs, including polyketides, non-ribosomal peptides, terpenoids, and alkaloids. The distribution of articles published per compound shows a bias toward the study of certain popular compounds, such as the aflatoxins. Phylogenetic analysis of biosynthetic genes suggests that much chemical and enzymatic diversity remains to be discovered in fungi. Our catalog was incorporated into the recently launched Minimum Information about Biosynthetic Gene cluster (MIBiG) repository to create the largest known set of fungal BGCs and associated NPs, a resource that we anticipate will guide future genome mining and synthetic biology efforts toward discovering novel fungal enzymes and metabolites. [ABSTRACT FROM AUTHOR]

Species of the fungus Fusarium collectively cause disease on almost all crop plants and produce numerous natural products (NPs), including some of the mycotoxins of greatest concern to agriculture. Many Fusarium NPs are derived from polyketide synthases (PKSs), large multi-domain enzymes that catalyze sequential condensation of simple carboxylic acids to form polyketides. To gain insight into the biosynthesis of polyketide-derived NPs in Fusarium , we retrieved 488 PKS gene sequences from genome sequences of 31 species of the fungus. In addition to these apparently functional PKS genes, the genomes collectively included 81 pseudogenized PKS genes. Phylogenetic analysis resolved the PKS genes into 67 clades, and based on multiple lines of evidence, we propose that homologs in each clade are responsible for synthesis of a polyketide that is distinct from those synthesized by PKSs in other clades. The presence and absence of PKS genes among the species examined indicated marked differences in distribution of PKS homologs. Comparisons of Fusarium PKS genes and genes flanking them to those from other Ascomycetes provided evidence that Fusarium has the genetic potential to synthesize multiple NPs that are the same or similar to those reported in other fungi, but that have not yet been reported in Fusarium . The results also highlight ways in which such analyses can help guide identification of novel Fusarium NPs and differences in NP biosynthetic capabilities that exist among fungi. [ABSTRACT FROM AUTHOR]

Despite the recent introduction of mass detection techniques, ultraviolet detection is still widely applied in the field of the chromatographic analysis of natural medicines. Here, a neural network cascade model consisting of nine small artificial neural network units was innovatively developed to predict the chromatographic sequence of natural compounds by integrating five molecular descriptors as the input. A total of 117 compounds of known structure were collected for model building. The order of appearance of each compound was determined in gradient chromatography. Strong linear correlation was found between the predicted and actual chromatographic position orders (Spearman's rho = 0.883, p < 0.0001). Application of the model to the external validation set of nine natural compounds was shown to dramatically increase the prediction accuracy of the real chromatographic order of multiple compounds. A case study shows that chromatographic sequence prediction based on a neural network cascade facilitated compound identification in the chromatographic fingerprint of Radix Salvia miltiorrhiza. For natural medicines of known compound composition, our method provides a feasible means for identifying the constituents of interest when only ultraviolet detection is available. [ABSTRACT FROM AUTHOR]

An efficient synthetic strategy to access hydroxyl-isochromanone and -isobenzofurans from readily available joint alkene precursors by a regiodivergent one-pot iodocyclization-substitution tandem process is reported. The cyclizations proceed with excellent diastereoselectivities, with E-alkenes giving syn-configured products and Z-alkenes giving anti-products. A strong influence of light on the regioselectivity of the reaction was observed. High yields were also observed under radical conditions. The protective-group-free method enables a highly concise synthesis of the authentic isochromanone core of the ajudazols, which are highly potent inhibitors of the mitochondrial respiratory chain. [ABSTRACT FROM AUTHOR]

Background: Heterologous production of natural products in Escherichia coli has emerged as an attractive strategy to obtain molecules of interest. Although technically feasible most of them are still constrained to laboratory scale production. Therefore, it is necessary to develop reasonable scale-up strategies for bioprocesses aiming at the overproduction of targeted natural products under industrial scale conditions. To this end, we used the production of the antibiotic valinomycin in E. coli as a model system for scalable bioprocess development based on consistent fed-batch cultivations. Results: In this work, the glucose limited fed-batch strategy based on pure mineral salt medium was used throughout all scales for valinomycin production. The optimal glucose feed rate was initially detected by the use of a biocatalytically controlled glucose release (EnBase® technology) in parallel cultivations in 24-well plates with continuous monitoring of pH and dissolved oxygen. These results were confirmed in shake flasks, where the accumulation of valinomycin was highest when the specific growth rate decreased below 0.1 h-1. This correlation was also observed for high cell density fed-batch cultivations in a lab-scale bioreactor. The bioreactor fermentation produced valinomycin with titers of more than 2 mg L-1 based on the feeding of a concentrated glucose solution. Valinomycin production was not affected by oscillating conditions (i.e. glucose and oxygen) in a scale-down two-compartment reactor, which could mimic similar situations in industrial bioreactors, suggesting that the process is very robust and a scaling of the process to a larger industrial scale appears a realistic scenario. Conclusions: Valinomycin production was scaled up from mL volumes to 10 L with consistent use of the fed-batch technology. This work presents a robust and reliable approach for scalable bioprocess development and represents an example for the consistent development of a process for a heterologously expressed natural product towards the industrial scale. [ABSTRACT FROM AUTHOR]

Natural product discovery from environmental genomes (metagenomics) has largely been limited to the screening of existing environmental DNA (eDNA) libraries. Here, we have coupled a chemical-biogeographic survey of chromopyrrolic acid synthase (CPAS) gene diversity with targeted eDNA library production to more efficiently access rare tryptophan dimer (TD) biosynthetic gene clusters. A combination of traditional and synthetic biology-based heterologous expression efforts using eDNA-derived gene clusters led to the production of hydroxysporine ( l) and reductasporine (2), two bioactive TDs. As suggested by our phylogenetic analysis of CPAS genes, identified in our survey of crude eDNA extracts, reductasporine (2) contains an unprecedented TD core structure: a pyrrolinium indolocarbazole core that is likely key to its unusual bioactivity profile. This work demonstrates the potential for the discovery of structurally rare and biologically interesting natural products using targeted metagenomics, where environmental samples are prescreened to identify the most phylogenetically unique gene sequences and molecules associated with these genes are accessed through targeted metagenomic library construction and heterologous expression. [ABSTRACT FROM AUTHOR]

Highlights: [•] Recombinant microorganisms offer an alternative for generating natural products. [•] Metabolic engineering requires optimization of regulatory processes within cells. [•] Theoretical methods allow the identification of genetic targets for optimization. [Copyright &y& Elsevier]

Highlights: [•] Natural products are advancing a dynamic comeback in drug discovery. [•] Advances in NMR play a vital role in the identification of natural products. [•] Improvements in NMR probes, experiments, data mining, and databases offer solutions. [•] Dereplication and metabolomics are integrated in modern natural products chemistry. [Copyright &y& Elsevier]

Zügige enantioselektive Totalsynthesen der Transtaganolide A – D gelingen mithilfe einer hoch diastereoselektiven Ireland ‐ Claisen/Diels ‐ Alder ‐ Reaktionskaskade ausgehend von einem enantiomerenangereicherten Geraniolderivat (siehe Schema). Auf der Grundlage von Röntgen ‐ Beugungsdaten wurde die absolute Konfiguration dieser Metabolite ermittelt und im Zusammenhang mit bestehenden Biosynthesemodellen diskutiert. [ABSTRACT FROM AUTHOR]

During the past few years, the production of natural value-added compounds from microbial sources has gained tremendous importance. Due to an increase in consumer demand for natural products, various food and pharmaceutical industries are continuously in search of novel metabolites obtained from microbial biotransformation. The exploitation of microbial biosynthetic pathways is both feasible and cost effective in the production of natural compounds. The environmentally compatible nature of these products is one major reason for their increasing demand. Novel approaches for natural product biogeneration will take advantage of the current studies on biotechnology, biochemical pathways and microbiology. The interest of the scientific community has shifted toward the use of microbial bioconversion for the production of valuable compounds from natural substrates. The present review focuses on eugenol biotransformation by microorganisms resulting in the formation of various value-added products such as ferulic acid, coniferyl alcohol, vanillin and vanillic acid. [ABSTRACT FROM AUTHOR]

Polyene macrolides are a large family of natural products typically produced by soil actinomycetes. Polyene macrolides are usually biosynthesized by modular and large type I polyketide synthases (PKSs), followed by several steps of sequential post-PKS modifications such as region-specific oxidations and glycosylations. Although known as powerful antibiotics containing potent antifungal activities (along with additional activities against parasites, enveloped viruses and prion diseases), their high toxicity toward mammalian cells and poor distribution in tissues have led to the continuous identification and structural modification of polyene macrolides to expand their general uses. Advances in in-depth investigations of the biosynthetic mechanism of polyene macrolides and the genetic manipulations of the polyene biosynthetic pathways provide great opportunities to generate new analogues. Recently, a novel class of polyene antibiotics was discovered (a disaccharide-containing NPP) that displays better pharmacological properties such as improved water-solubility and reduced hemolysis. In this review, we summarize the recent advances in the biosynthesis, pathway engineering, and regulation of polyene antibiotics in actinomycetes. [ABSTRACT FROM AUTHOR]

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Abstract: Objective: To evaluate the antifungal activity of four honeys of different types from Algeria against pathogenic yeast i.e. Candida albicans (C. albicans) and Rhodotorula sp. Methods: Four Algeria honeys of different botanical origin were analyzed to test antifungal effect against C. albicans, and Rhodotorula sp. Different concentrations (undiluted, 10%, 30%, 50% and 70% w/v) of honey were studied in vitro for their antifugal activity using C. albicans and Rhodotorula sp. as fungal strains. Results: The range of the diameter of zone of inhibition of various concentrations of tested honeys was (7–23 mm) for Rhodotorula sp., while C. albicans showed clearly resistance towards all concentrations used. The MICs of tested honey concentrations against C. albicans and Rhodotorula sp. were (70.09–93.48)% and (4.90–99.70)% v/v, respectively. Conclusions: This study demonstrates that, in vitro, these natural products have clearly an antifungal activity against Rhodotorula sp. and C. albicans. [Copyright &y& Elsevier]

Abstract: In an effort to improve the aqueous solubility and the antitumor activity of natural product asperphenamate, we have designed and synthesized three series of asperphenamate derivatives, including series I (simplifying molecular skeleton series), series II (introducing a hydroxyl group to A-phenyl ring series) and series III (disrupting molecular planarity series). All derivatives have displayed a significantly increased solubility compared with asperphenamate. Their growth inhibitory activities in vitro were screened by the standard MTT method in MCF-7, HeLa, and BEL-7402 cell lines. With the exception of the derivatives in series I, most of derivatives in series II and series III showed growth inhibitory activity. Among all derivatives, IM23b in series III showed the greatest potency in human breast cancer MCF-7 cells. The cellular potency of IM23b was approximately 1.5-fold more potent than that of cisplatin. The mechanism of cell death induced by IM23b in human breast cancer MCF-7 cells was further investigated. We concluded that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest. [Copyright &y& Elsevier]

Abstract: Currently, one third of the world’s population is infected with Mycobacterium tuberculosis and 8.9–9.9 million new and relapse cases of tuberculosis are reported every year. The emergence of new cases, the increased incidence of multi-drug resistant strains of M. tuberculosis, and the adverse effects of first- and second-line antituberculosis drugs have led to renewed research interest in natural products in the hope of discovering new antitubercular leads. Interestingly, hundreds of natural products, possessing novel, uncommon, and known structural architectures, have been reported to exhibit activity towards non-resistant and multi-drug resistant strains of M. tuberculosis. The present review covers literature published during the last five years about those naturally occurring compounds with reported growth inhibitory activity in vitro towards sensitive and resistant M. tuberculosis strains. Compounds with antitubercular properties at minimal inhibitory concentrations (MICs) of less than 50 μg/mL or 60 μM were selected and grouped according to their source of origin (plants, bacteria, fungi, marine organisms, etc) and chemical type (terpenes, steroids, alkaloids, flavonoids, poliketides, peptides, etc). In some cases, the selection covers those structurally relevant natural products with low bioactivity (MICs of ≤128 μg/mL), and also those semisynthetic derivatives with remarkable antitubercular activity (MICs of ≤10 μg/mL). Additionally, this review includes a special section for those natural products that specifically target genes or enzymes of M. tuberculosis. [Copyright &y& Elsevier]

Plant triterpenoids represent a large and structurally diverse class of natural products. A growing interest has been focused on triterpenoids over the past decade due to their beneficial effects on human health. We show here that these bioactive compounds are major constituents of several aerial parts (floral bud, leaf bud, stem, and leaf) of olive tree, a crop exploited so far almost exclusively for its fruit and oil. O. europaea callus cultures were analyzed as well. Twenty sterols and twenty-nine nonsteroidal tetraand pentacyclic triterpenoids belonging to seven types of carbon skeletons (oleanane, ursane, lupane, taraxerane, taraxastane, euphane, and lanostane) were identified and quantified by GC and GC-MS as free and esterified compounds. The oleanane-type compounds, oleanolic acid and maslinic acid, were largely predominant in all the organs tested, whereas they are practically absent in olive oil. In floral buds, they represented as much as 2.7% of dry matter. In callus cultures, lanostane-type compounds were the most abundant triterpenoids. In all the tissues analyzed, free and esterified triterpene alcohols exhibited different distribution patterns of their carbon skeletons. Taken together, these data provide new insights into largely unknown triterpene secondary metabolism of Olea europaea. [ABSTRACT FROM AUTHOR]

Fibrosterol sulfate A is a polysulfated bis-steroid with an atypical side chain. Due to the flexibility of the linker, large-scale motions that change dramatically the shape of the entire molecule are expected. Such motions pose major challenges to the structure elucidation and the correct determination of configuration. In this study, we will describe the determination of the relative configuration of fibrosterol sulfate A through a residual dipolar coupling based multiple alignment tensor analysis complemented by molecular dynamics. For completeness, we applied also the single tensor approach which is unreliable due to the large-scale motions and compare the results. [ABSTRACT FROM AUTHOR]

Natural products have always been a major source of therapeutic agents; however, the development of traditional herbal products has been currently hampered by the lack of analytic methods suitable for both high-throughput screening and evaluating the mechanism of action. Cellular processes such as proliferation, apoptosis, and toxicity are well-orchestrated in real time. Monitoring these events and their perturbation by natural products can provide high-rich information about cell physiological relevancies being involved. Here, we report a novel cell-based phenotypic profiling strategy that uses electronic impedance readouts for real-time monitoring of cellular responses to traditional Chinese medicines (TCMs). The utility of this approach was used to screen natural herbs that have been historically documented to cure human diseases and that have been classified into seven clusters based on their mechanisms of action. The results suggest that herbal medicines with similar cellular mechanisms produce similar time/dose-dependent cell response profiles (TCRPs). By comparing the TCRPs produced by the Chinese medicinal Cordyceps sinensis with similar TCRPs of chemical compounds, we explored the potential use of herbal TCRPs for predicting cellular mechanisms of action, herbal authentications, and bioactive identification. Additionally, we further compared this novel TCRP technology with high-performance liquid chromatography (HPLC)-based methods for herbal origin-tracing authentication and identification of bioactive ingredients. Together, our findings suggest that using TCRP as an alternative to existing spectroscopic techniques can allow us to analyze natural products in a more convenient and physiologically relevant manner. [ABSTRACT FROM AUTHOR]

Neuro-enhancement refers to the use of applications of modern neurosciences to make people better - smarter, happier, more sociable etc. This paper consists of analyses on claims concerning unnaturalness of neuro-enhancement. In what sense, if any, is neuro-enhancement unnatural? If neuro-enhancement is unnatural, is its unnaturalness morally noteworthy? Four possible senses of naturalness are analyzed: naturalness as normality, naturalness as suitability, naturalness as belonging, and naturalness as familiarity. None of these interpretations offers sufficient support for the view that neuro-enhancement is morally problematic because of its unnaturalness. [ABSTRACT FROM AUTHOR]

Lithistid sponges have been an important source of structurally complex natural products with potent biological activities. Examples of compounds marketed as biological markers along with recent advances in defining the modes of action and biomedical potential of lithistid-derived compounds are presented. [ABSTRACT FROM AUTHOR]

Methods used to evaluate the effectiveness of cleaning and disinfection regimes, or of putative antimicrobial surfaces, rely on an estimate of the amount of viable microbial cells remaining on a surface after treatment. In essence, microbial cells are applied to the surface, and the number remaining after a specified time/treatment is assessed by variety of methods. This paper provides a critical commentary on these methods. The most common method relies on removal of the cells from the surface, by swabbing or agitation, plating onto culture media, and counting the number of colonies obtained. However, the surface should always be subsequently examined for residual cells: low numbers of colonies are deemed indicative of effective cleaning (i.e. few cells on the surface), but they could also indicate that cells have not been removed from the surface. Swabbing efficiency can be affected by moisture at the surface, presence of organic material, surface topography and presence of antimicrobial compounds. It is important to be aware of the limitations of a given method for assessing the presence of microorganisms on a surface, as well as of the intended antimicrobial property of the surface or agent applied to the surface. [ABSTRACT FROM AUTHOR]

Abstract: This paper describes two experiments conducted to examine the acaricidal potential of spinosad against the poultry red mite, Dermanyssus gallinae (De Geer), a serious ectoparasitic pest of laying hens. Spinosad is a natural product derived from the fermentation of the micro-organism Saccharopolyspora spinosa. In vitro testing confirmed that, when applied to a galvanised metal plate to the point of run-off, spinosad was toxic to adult female D. gallinae and suggested that at an application rate of 3.88g/L a significant residual toxicity of spinosad could be achieved for up to 21 days. A subsequent in vivo experiment in a conventional cage housing system for laying hens demonstrated the acaricidal activity and residual toxicity to D. gallinae of a single application of spinosad when applied at either 1.94 or 3.88g/L. Residual toxicity of spinosad at both of these application rates was maintained throughout the course of the 28 day post-spray study period, with a peak in product efficacy seen 14 days after spraying. The results suggest that the greater the D. gallinae population the greater will be the toxic effect of spinosad. Although the exact reasons for this are unclear, it can be speculated that conspecifics spread the product between each other more efficiently at higher mite population densities. However, further study is warranted to confirm this possibility. Application of spinosad in vivo had no effect on hen bodyweight or egg production parameters (number and weight), suggesting that this product could be used to effectively control D. gallinae infestations whilst birds are in lay. This paper also describes a novel method for effectively and efficiently achieving replication of treatments in a single poultry house, previously unpopulated with D. gallinae. Individual groups of conventional cages were stocked with hens, seeded with D. gallinae and used as replicates. Independence of replicates was achieved by isolating cage groups from one another using a non-drying glue barrier to minimise D. gallinae migration. Creating isolated populations (replicates) of D. gallinae within a single poultry house thus represents a novel and efficient means of screening other potential acaricides under field conditions. [Copyright &y& Elsevier]

Abstract: The enzyme MurA performs an essential step in peptidoglycan biosynthesis and is therefore a target for the discovery of novel antibacterial compounds. We report here the inhibition of MurA by natural products from tulips (tulipalines and tuliposides), and the structure–activity relationships of various derivatives. The inhibition of MurA can be related to antibacterial activity, and MurA is probably one of the relevant molecular targets of the tulipaline derivatives. MurA inhibition by this class of compounds depends on the presence of the substrate UNAG, which indicates non-covalent suicide inhibition as observed previously for cnicin. With respect to selectivity, however, the reactivity against arbitrary sulfhydryl groups, such as in glutathione, could not yet be sufficiently separated from MurA inhibition in the present dataset. [Copyright &y& Elsevier]

Abstract: Three antimalarial meroditerpenes have been isolated from two Fijian red macroalgae. The absolute stereochemistry of callophycolide A (1), a unique macrolide from Callophycus serratus, was determined using a combination of Mosher’s ester analysis, circular dichroism analysis with a dimolybdenum tetraacetate complex, and conformational analysis using NOEs. In addition, two known tocopherols, β-tocopherylhydroquinone (4) and δ-tocopherylhydroquinone (5), were isolated from Amphiroa crassa. By oxidizing 5 to the corresponding δ-tocopherylquinone (6), antimalarial activity against the human malaria parasite Plasmodium falciparum was increased by more than 20-fold. [Copyright &y& Elsevier]

Abstract: The anthelmintic activity of extracts from Chenopodium ambrosioides, Pycnanthus angolensis and Nutridesintox® was in vitro and in vivo investigated, against Toxocara canis larvae. The in vitro assays results showed that the aqueous extract of Nutridesintox® was the most effective, followed by C. ambrosioides extracts, hexane, dichloromethane and the infusion. P. angolensis extracts showed a lower anthelmintic activity compared to the other natural products. For the in vivo assays, Nutridesintox®, the hexane extract and the infusion of C. ambrosioides were administered orally to T. canis-infected mice, in single doses, during three consecutive days. The efficacy was evaluated on the 17th day post-infection, not only by counting T. canis larvae in the tissues but also by ELISA detection of IgM and IgG antibodies and histological analysis of liver and lungs. The different treatments did not reduce the larvae burden and had no influence on the antibodies dynamic. Interestingly, a reduction on the inflammatory infiltrates was observed in the liver and lung sections of the group treated with the hexane extract of C. ambrosioides. In conclusion, the hexane extract of C. ambrosioides is of further research interest, as it showed an anthelmintic activity in vitro and a reduction on the inflammatory reaction produced by the infection of T. canis larvae in vivo. [ABSTRACT FROM AUTHOR]