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Bulb, leaf, scape and flower samples of British bluebells ( Hyacinthoides non-scripta ) were collected regularly for one growth period. Methanolic extracts of freeze-dried and ground samples showed antitrypanosomal activity, giving more than 50% inhibition, for 20 out of 41 samples. High-resolution mass spectrometry was used in the dereplication of the methanolic extracts of the different plant parts. The results revealed differences in the chemical profile with bulb samples being distinctly different from all aerial parts. High molecular weight metabolites were more abundant in the flowers, shoots and leaves compared to smaller molecular weight ones in the bulbs. The anti-trypanosomal activity of the extracts was linked to the accumulation of high molecular weight compounds, which were matched with saponin glycosides, while triterpenoids and steroids occurred in the inactive extracts. Dereplication studies were employed to identify the significant metabolites via chemotaxonomic filtration and considering their previously reported bioactivities. Molecular networking was implemented to look for similarities in fragmentation patterns between the isolated saponin glycoside at m / z 1445.64 [M + formic-H] − equivalent to C 64 H 104 O 33 and the putatively found active metabolite at m / z 1283.58 [M + formic-H] − corresponding to scillanoside L-1. A combination of metabolomics and bioactivity-guided approaches resulted in the isolation of a norlanostane-type saponin glycoside with antitrypanosomal activity of 98.9% inhibition at 20 µM.

Professor Tu Youyou is a renowned Chinese scientist whose pioneering work led to the discovery in the 1970s of the antimalarial sesquiterpene lactone, artemisinin (qinghaosu), from the sweet wormwood tree, Artemisia annua L [...]

Key Points Natural products continue to be an important source of leads for new medicines, despite reduced interest from large pharmaceutical companies. Screening collections of natural products can be assembled economically to provide excellent coverage of drug-like chemical space and in formats that are compatible with high-throughput bioassays. Metabolomics enables the rapid identification of novel compounds in complex mixtures of natural products and also provides a means to monitor the production of target molecules during fermentation or other production processes. Metagenomics and other genetic engineering techniques are enabling the production of target compounds in convenient systems, breaking away from the bottleneck otherwise created by microorganisms that are difficult to culture. Examples of recent and current applications of natural products are described for the discovery of antimicrobials and for inhibitors of protein–protein interactions, particularly as anticancer agents. The screening of natural products for lead molecules is an attractive strategy, as most natural products fall within biologically relevant chemical space. In this Review, Harvey, Edrada-Ebel and Quinn discuss how advanced screening, metabolomics and metagenomics approaches can be used in the identification, validation and production of naturally sourced compounds, and highlight examples of naturally derived antimicrobials and inhibitors of protein–protein interactions. Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein–protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

Macrocystis pyrifera and Lessonia spicata are economically and ecologically relevant brown seaweeds that recently have been classified as members of two separated families within Laminariales (kelps). Here we describe for the first time the Macrocystis pyrifera x Lessonia spicata hybridization in the wild (Chiloe Island, Southeastern Pacific), where populations of the two parents exist sympatrically. Externally, this hybrid exhibited typical features of its parents M. pyrifera (cylindrical and flexible distal stipes, serrate frond margins and presence of sporophylls) and L. spicata (rigid and flat main stipe and first bifurcation), as well as intermediate features between them (thick unfused haptera in the holdfast). Histological sections revealed the prevalence of mucilage ducts within stipes and fronds (absent in Lessonia ) and fully developed unilocular sporangia in the sporophylls. Molecular analyses confirmed the presence of the two parental genotypes for ITS1 nrDNA and the M. pyrifera genotype for two predominantly maternally inherited cytoplasmic markers (COI and rbc LS spacer) in the tissue of the hybrid. A metabolome-wide approach revealed that this hybrid is more chemically reminiscent to M. pyrifera . Nevertheless, several hits were identified as Lessonia exclusive or more remarkably, not present in any of the parent. Meiospores developed into apparently fertile gametophytes, which gave rise to F1 sporophytes that reached several millimeters before suddenly dying. In-vitro reciprocal crossing of Mar Brava gametophytes from both species revealed that although it is rare, interfamilial hybridization between the two species is possible but mostly overcome by pseudogamy of female gametophytes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of fumarate caused by the inactivation of FH leads to oxidative stress that is mediated by the formation of succinicGSH, a covalent adduct between fumarate and glutathione. Chronic succination of GSH, caused by the loss of FH, or by exogenous fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo . Importantly, the ablation of p21, a key mediator of senescence, in Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that fumarate-induced senescence needs to be bypassed for the initiation of renal cancers. Fumarate hydratase (FH) mutations are associated with renal cancer. Here, Zheng et al . use metabolomic and analytical chemistry approaches to reveal that fumarate accumulated due to FH loss covalently modifies intracellular glutathione, leading to oxidative stress and senescence.

Contamination of food and feed by Aflatoxin B1 (AFB1) is a cause of serious economic and health problems. Different processes have been used to degrade AFB1. In this study, biological degradation of AFB1 was carried out using three Actinomycete species, Rhodococcus erythropolis ATCC 4277, Streptomyces lividans TK 24, and S. aureofaciens ATCC 10762, in liquid cultures. Biodegradation of AFB1 was optimised under a range of temperatures from 25 to 40 °C and pH values of 4.0 to 8.0. An initial concentration of 20 µg/mL of AFB1 was used in this study. The amount of AFB1 remaining was measured against time by thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC), coupled with UV and mass spectrometry (LC-MS). All species were able to degrade the AFB1, and no significant difference was found between them. AFB1 remained in the liquid culture for R. erythropolis, S. lividans and S. aureofaciens were 0.81 µg/mL, 2.41 µg/mL and 2.78 µg/mL respectively, at the end of the first 24 h. Degradation occurred at all incubation temperatures and the pH with the optimal conditions for R. erythropolis was achieved at 30 °C and pH 6, whereas for S. lividans and S. aureofaciens the optimum conditions for degradation were 30 °C and pH 5. Analysis of the degradative route indicated that each microorganism has a different way of degrading AFB1. The metabolites produced by R. erythropolis were significantly different from the other two microorganisms. Products of degradation were identified through metabolomic studies by utilizing high-resolution mass spectral data. Mass spectrometric analysis indicated that the degradation of AFB1 was associated with the appearance of a range of lower molecular weight compounds. The pathway of degradation or chemical alteration of AFB1 was followed by means of high resolution Fourier transform mass spectrometry (HR-FTMS) analysis as well as through the MS2 fragmentation to unravel the degradative pathway for AFB1. AFB1 bio-degradation was coupled with the accumulation of intermediates of fatty acid metabolism and glycolysis. A plausible mechanism of degradation of AFB1 by Rhodococcus was hypothesized.

The discovery of new secondary metabolites from natural origins has become more challenging in natural products research. Different approaches have been applied to target the isolation of new bioactive metabolites from plant extracts. In this study, bioactive natural products were isolated from the crude organic extract of the mangrove plant Avicennia lanata collected from the east coast of Peninsular Malaysia in the Setiu Wetlands, Terengganu, using HRESI-LCMS-based metabolomics-guided isolation and fractionation. Isolation work on the crude extract A. lanata used high-throughput chromatographic techniques to give two new naphthofuranquinone derivatives, hydroxyavicenol C (1) and glycosemiquinone (2), along with the known compounds avicenol C (3), avicequinone C (4), glycoquinone (5), taraxerone (6), taraxerol (7), β-sitosterol (8) and stigmasterol (9). The elucidation and identification of the targeted bioactive compounds used 1D and 2D-NMR and mass spectrometry. Except for 6–9, all isolated naphthoquinone compounds (1–5) from the mangrove plant A. lanata showed significant anti-trypanosomal activity on Trypanosoma brucei brucei with MIC values of 3.12–12.5 μM. Preliminary cytotoxicity screening against normal prostate cells (PNT2A) was also performed. All compounds exhibited low cytotoxicity, with compounds 3 and 4 showing moderate cytotoxicity of 78.3% and 68.6% of the control values at 100 μg/mL, respectively.

High resolution Fourier transform mass spectrometry (HRFTMS) and nuclear magnetic resonance (NMR) spectroscopy were employed as complementary metabolomic tools to dereplicate the chemical profile of the new and antitrypanosomally active sponge-associated bacterium Actinokineospora sp. EG49 extract. Principal Component (PCA), hierarchical clustering (HCA), and orthogonal partial least square-discriminant analysis (OPLS-DA) were used to evaluate the HRFTMS and NMR data of crude extracts from four different fermentation approaches. Statistical analysis identified the best culture one-strain-many-compounds (OSMAC) condition and extraction procedure, which was used for the isolation of novel bioactive metabolites. As a result, two new O-glycosylated angucyclines, named actinosporins A (1) and B (2), were isolated from the broth culture of Actinokineospora sp. strain EG49, which was cultivated from the Red Sea sponge Spheciospongia vagabunda. The structures of actinosporins A and B were determined by 1D- and 2D-NMR techniques, as well as high resolution tandem mass spectrometry. Testing for antiparasitic properties showed that actinosporin A exhibited activity against Trypanosoma brucei brucei with an IC50 value of 15 µM; however no activity was detected against Leishmania major and Plasmodium falciparum, therefore suggesting its selectivity against the parasite Trypanosoma brucei brucei; the causative agent of sleeping sickness.

Literature surveys, taxonomical differences, and bioassay results have been utilized in the discovery of new natural products to aid in Actinomycetes isolate-selection. However, no or less investigation have been done on establishing the differences in metabolomic profiles of the isolated microorganisms. The study aims to utilise bioassay- and metabolomics-guided tools that included dereplication study and multivariate analysis of the NMR and mass spectral data of microbial extracts to assist the selection of isolates for scaling-up the production of antimicrobial natural products. A total of 58 actinomycetes were isolated from different soil samples collected from Ihnasia City, Egypt and screened for their antimicrobial activities against indicator strains that included Bacillus subtilis, Escherichia coli, methicillin-resistant Staphylococcus aureus and Candida albicans. A number of 25 isolates were found to be active against B. subtilis and/or to at least one of the tested indicator strains. Principal component analyses showed chemical uniqueness for four outlying bioactive actinomycetes extracts. In addition, Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) and dereplication study led us to further select two outlying anti-MRSA active isolates MS.REE.13 and 22 for scale-up work. MS.REE.13 and 22 exhibited zones of inhibition at 19 and 13 mm against MRSA, respectively. A metabolomics-guided approach provided the steer to target the bioactive metabolites (P<0.01) present in a crude extract or fraction even at nanogram levels but it was a challenge that such low-yielding bioactive natural products would be feasible to isolate. Validated to occur only on the active side of OPLS-DA loadings plot, the isolated compounds exhibited medium to weak antibiotic activity with MIC values between 250 and 800 μM. Two new compounds, P_24306 (C10H13N2) and N_12799 (C18H32O3) with MICs of 795 and 432 μM, were afforded from the scale-up of MS.REE. 13 and 22, respectively.