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Metabolites
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Application of Metabolomics in Characterization of Novel Bioactive Natural Products
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Application of Metabolomics in Characterization of Novel Bioactive Natural Products

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Metabolomic Profiling Technology".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 12680

Special Issue Editor

Dr. Constanze Müller

E-Mail Website1 Website2
Guest Editor
German Research Center for Environmental Health, Institute of Environmental Medicine, Helmholtz Zentrum München, D-85764 Neuherberg, Germany
Interests: ultra-high resolution tools; non-targeted metabolomics; bioactives; natural products; cell painting; data science

Special Issue Information

Dear Colleagues,

Living organisms produce bioactive molecules for defense or adaption to their environment; so-called natural products. These have been used for millennia, for example, as flavors and dyes, or in traditional medicine. Despite the large number of natural products already known, unexplored biodiversity is far from being exhausted, due to various reasons such as difficult screening, identification, and complex synthesis or extraction in low yields. Currently, the paradigm of natural product discovery needs to be re-examined considering the technological progress that has been made. Metabolomics combined with sophisticated data mining and advanced activity assays can greatly accelerate bioactivity screenings, guide chemical analysis, and improve de-replication.  Moreover, metabolites are themselves biochemical interactors. They often modify multiple targets and lead to complex changes of metabolic networks. In many diseases, intertwined metabolic networks are found and lead to multi-layered pathophysiology. Natural products and their complex extracts act on multiple targets and offer the opportunity to study and modify such network effects.

Dr. Constanze Müller
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metabolomics
  • hit discovery
  • data integration/-science
  • traditional medicines
  • poly-pharmaceutical networks
  • phenotypic screenings
  • (non-)targeted assays
  • single cell
  • metabolic modeling
  • bioinformatics-guided identification

Published Papers (5 papers)

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Research

23 pages, 6216 KiB  
Article
Bioactive Efficacy of Novel Carboxylic Acid from Halophilic Pseudomonas aeruginosa against Methicillin-Resistant Staphylococcus aureus
by Henciya Santhaseelan, Vengateshwaran Thasu Dinakaran, Balasubramaniyan Sakthivel, Maharaja Somasundaram, Kaviarasan Thanamegam, Velmurugan Devendiran, Hans-Uwe Dahms and Arthur James Rathinam
Metabolites 2022, 12(11), 1094; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12111094 - 10 Nov 2022
Cited by 5 | Viewed by 1529
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) infections are increasingly causing morbidity and mortality; thus, drugs with multifunctional efficacy against MRSA are needed. We extracted a novel compound from the halophilic Pseudomonas aeruginosa using an ethyl acetate (HPAEtOAcE). followed by purification and structure elucidation through HPLC, [...] Read more.
Methicillin-resistant Staphylococcus aureus (MRSA) infections are increasingly causing morbidity and mortality; thus, drugs with multifunctional efficacy against MRSA are needed. We extracted a novel compound from the halophilic Pseudomonas aeruginosa using an ethyl acetate (HPAEtOAcE). followed by purification and structure elucidation through HPLC, LCMS, and 1H and 13C NMR, revealing the novel 5-(1H-indol-3-yl)-4-pentyl-1,3-oxazole-2-carboxylic acid (Compound 1). Molecular docking of the compound against the MRSA PS (pantothenate synthetase) protein was confirmed using the CDOCKER algorithm in BDS software with specific binding to the amino acids Arg (B:188) and Lys (B:150) through covalent hydrogen bonding. Molecular dynamic simulation of RMSD revealed that the compound–protein complex was stabilized. The proficient bioactivities against MRSA were attained by the HPAEtOAcE, including MIC and MBCs, which were 0.64 and 1.24 µg/mL, respectively; 100% biomass inhibition and 99.84% biofilm inhibition were observed with decayed effects by CLSM and SEM at 48 h. The hla, IrgA, and SpA MRSA genes were downregulated in RT-PCR. Non-hemolytic and antioxidant potential in the DPPH assay were observed at 10 mg/mL and IC50 29.75 ± 0.38 by the HPAEtOAcE. In vitro growth inhibition assays on MRSA were strongly supported by in silico molecular docking; Lipinski’s rule on drug-likeness and ADMET toxicity prediction indicated the nontoxic nature of compound. Full article
(This article belongs to the Special Issue Application of Metabolomics in Characterization of Novel Bioactive Natural Products)
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15 pages, 2223 KiB  
Article
Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression
by Carlos Guijas, Lucy E. Horton, Linh Hoang, Xavier Domingo-Almenara, Elizabeth M. Billings, Brian C. Ware, Brian Sullivan and Gary Siuzdak
Metabolites 2022, 12(7), 645; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12070645 - 14 Jul 2022
Cited by 5 | Viewed by 2428
Abstract
The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8+ T cells, reveal [...] Read more.
The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8+ T cells, reveal a potential role of 3-IPA in these responses. T-cell exhaustion was examined via infection of two genetically related mouse strains, DBA/1J and DBA/2J, with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13). The different mouse strains produced disparate outcomes driven by their T-cell responses. Infected DBA/2J presented with exhausted T cells and persistent infection, and DBA/1J mice died one week after infection from cytotoxic T lymphocytes (CTLs)-mediated pulmonary failure. Metabolomics revealed over 70 metabolites were altered between the DBA/1J and DBA/2J models over the course of the infection, most of them in mice with a fatal outcome. Cognitive-driven prioritization combined with statistical significance and fold change were used to prioritize the metabolites. 3-IPA, a tryptophan-derived metabolite, was identified as a high-priority candidate for testing. To test its activity 3-IPA was added to the drinking water of the mouse models during LCMV Cl13 infection, with the results showing that 3-IPA allowed the mice to survive longer. This negative immune-modulation effect might be of interest for the modulation of CTL responses in events such as autoimmune diseases, type I diabetes or even COVID-19. Moreover, 3-IPA’s bacterial origin raises the possibility of targeting the microbiome to enhance CTL responses in diseases such as cancer and chronic infection. Full article
(This article belongs to the Special Issue Application of Metabolomics in Characterization of Novel Bioactive Natural Products)
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16 pages, 2670 KiB  
Article
Untargeted Metabolomics Combined with Solid Phase Fractionation for Systematic Characterization of Bioactive Compounds in Hemp with Methane Mitigation Potential
by Rikke Hald Jensen, Marie Rønn, Mirka Thorsteinsson, Dana W. Olijhoek, Mette Olaf Nielsen and Natalja P. Nørskov
Metabolites 2022, 12(1), 77; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12010077 - 13 Jan 2022
Cited by 3 | Viewed by 2160
Abstract
This study systematically evaluates the presence of methane mitigating metabolites in two hemp (Cannabis sativa L.) varieties, Futura 75 and Finola. Hemp metabolites were extracted with methanol and fractionated using Solid Phase Extraction (SPE). Extracts, fractions, and the remaining pulp were [...] Read more.
This study systematically evaluates the presence of methane mitigating metabolites in two hemp (Cannabis sativa L.) varieties, Futura 75 and Finola. Hemp metabolites were extracted with methanol and fractionated using Solid Phase Extraction (SPE). Extracts, fractions, and the remaining pulp were screened for their methane mitigating potential using an in vitro model of rumen fermentation. The bioactive metabolites were identified with Liquid Chromatography-Mass Spectrometry (LC-MS). When incubated with a standard feed (maize silage), the extract of Futura 75 significantly reduced methane production compared to that of control (without added extract) and without negative effects on feed degradability and volatile fatty acid patterns. The compounds responsible for the methane mitigating effect were assigned to flavonoid glycosides. However, none of the fractions of Futura 75 or the pulp exhibited similar effect on methane emission. Butyric acid concentration in the fermentation inoculum was significantly increased, which could indicate why methane production was higher, when incubated with the fractions and the pulp. The extract of Finola did not show a similar significant effect, however, there was a numerical tendency towards lower methane production. The difference in methane mitigating properties between Cannabis sativa L. Futura 75 and Finola, could be related to the content of bioactive flavonoids. Full article
(This article belongs to the Special Issue Application of Metabolomics in Characterization of Novel Bioactive Natural Products)
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18 pages, 3785 KiB  
Article
Mining for Active Molecules in Probiotic Supernatant by Combining Non-Targeted Metabolomics and Immunoregulation Testing
by Juliano Roldan Fonseca, Marianna Lucio, Mourad Harir and Philippe Schmitt-Kopplin
Metabolites 2022, 12(1), 35; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12010035 - 04 Jan 2022
Cited by 3 | Viewed by 2736
Abstract
Chronic respiratory diseases such as asthma are highly prevalent in industrialized countries. As cases are expected to rise, there is a growing demand for alternative therapies. Our recent research on the potential benefits of probiotics suggests that they could prevent and reduce the [...] Read more.
Chronic respiratory diseases such as asthma are highly prevalent in industrialized countries. As cases are expected to rise, there is a growing demand for alternative therapies. Our recent research on the potential benefits of probiotics suggests that they could prevent and reduce the symptoms of many diseases by modulating the host immune system with secreted metabolites. This article presents the first steps of the research that led us to identify the immunoregulatory bioactivity of the amino acid d-Trp reported in our previous study. Here we analyzed the cell culture metabolic footprinting of 25 commercially available probiotic strains to associate metabolic pathway activity information with their respective immune modulatory activity observed in vitro. Crude probiotic supernatant samples were processed in three different ways prior to untargeted analysis in positive and negative ionization mode by direct infusion ESI-FT-ICR-MS: protein precipitation and solid phase extraction (SPE) using HLB and CN-E sorbent cartridges. The data obtained were submitted to multivariate statistical analyses to distinguish supernatant samples into the bioactive and non-bioactive group. Pathway analysis using discriminant molecular features showed an overrepresentation of the tryptophan metabolic pathway for the bioactive supernatant class, suggesting that molecules taking part in that pathway may be involved in the immunomodulatory activity observed in vitro. This work showcases the potential of metabolomics to drive product development and novel bioactive compound discovery out of complex biological samples in a top-down manner. Full article
(This article belongs to the Special Issue Application of Metabolomics in Characterization of Novel Bioactive Natural Products)
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20 pages, 1848 KiB  
Article
Feature-Based Molecular Networking—An Exciting Tool to Spot Species of the Genus Cortinarius with Hidden Photosensitizers
by Fabian Hammerle, Luis Quirós-Guerrero, Adriano Rutz, Jean-Luc Wolfender, Harald Schöbel, Ursula Peintner and Bianka Siewert
Metabolites 2021, 11(11), 791; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11110791 - 19 Nov 2021
Cited by 3 | Viewed by 2513
Abstract
Fungi have developed a wide array of defense strategies to overcome mechanical injuries and pathogen infections. Recently, photoactivity has been discovered by showing that pigments isolated from Cortinarius uliginosus produce singlet oxygen under irradiation. To test if this phenomenon is limited to dermocyboid [...] Read more.
Fungi have developed a wide array of defense strategies to overcome mechanical injuries and pathogen infections. Recently, photoactivity has been discovered by showing that pigments isolated from Cortinarius uliginosus produce singlet oxygen under irradiation. To test if this phenomenon is limited to dermocyboid Cortinarii, six colourful Cortinarius species belonging to different classical subgenera (i.e., Dermocybe, Leprocybe, Myxacium, Phlegmacium, and Telamonia) were investigated. Fungal extracts were explored by the combination of in vitro photobiological methods, UHPLC coupled to high-resolution tandem mass spectrometry (UHPLC-HRMS2), feature-based molecular networking (FBMN), and metabolite dereplication techniques. The fungi C. rubrophyllus (Dermocybe) and C. xanthophyllus (Phlegmacium) exhibited promising photobiological activity in a low concentration range (1–7 µg/mL). Using UHPLC-HRMS2-based metabolomic tools, the underlying photoactive principle was investigated. Several monomeric and dimeric anthraquinones were annotated as compounds responsible for the photoactivity. Furthermore, the results showed that light-induced activity is not restricted to a single subgenus, but rather is a trait of Cortinarius species of different phylogenetic lineages and is linked to the presence of fungal anthraquinones. This study highlights the genus Cortinarius as a promising source for novel photopharmaceuticals. Additionally, we showed that putative dereplication of natural photosensitizers can be done by FBMN. Full article
(This article belongs to the Special Issue Application of Metabolomics in Characterization of Novel Bioactive Natural Products)
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