Genomic and Metabolomic Analysis of the Potato Common Scab Pathogen Streptomyces scabiei

Streptomyces scabiei is a key causative agent of common scab disease, which causes significant economic losses to potato growers worldwide. This organism produces several phytotoxins that are known or suspected to contribute to host–pathogen interactions and disease development; however, the full metabolic potential of S. scabiei has not been previously investigated. In this study, we used a combined metabolomic and genomic approach to investigate the metabolites that are produced by S. scabiei. The genome sequence was analyzed using antiSMASH and DeepBGC to identify specialized metabolite biosynthetic gene clusters. Using untargeted liquid chromatography-coupled tandem mass spectrometry (LC-MS2), the metabolic profile of S. scabiei was compared after cultivation on three different growth media. MS2 data were analyzed using Feature-Based Molecular Networking and hierarchical clustering in BioDendro. Metabolites were annotated by performing a Global Natural Products Social Molecular Networking (GNPS) spectral library search or using Network Annotation Propagation, SIRIUS, MetWork, or Competitive Fragmentation Modeling for Metabolite Identification. Using this approach, we were able to putatively identify new analogues of known metabolites as well as molecules that were not previously known to be produced by S. scabiei. To our knowledge, this study represents the first global analysis of specialized metabolites that are produced by this important plant pathogen

Metabolomics in Ecology and Bioactive Natural Products Discovery: Challenges and Prospects for a Comprehensive Study of the Specialised Metabolome

Metabolomics is playing an increasingly prominent role in chemical ecology and in the discovery of bioactive natural products (NPs). The identification of metabolites is a common/central objective in both research fields. NPs have significant biological properties and play roles in multiple chemical-ecological interactions. Classically, in pharmacognosy, their chemical structure is determined after a complex process of isolating and interpreting spectroscopic data. With the advent of powerful analytical techniques such as liquid chromatography-mass spectrometry (LC-MS) the annotation process of the specialised metabolome of plants and microorganisms has improved considerably. In this article, we summarise the possibilities opened by these advances and illustrate how we harnessed them in our own research to automate annotations of NPs and target the isolation of key compounds. In addition, we are also discussing the analytical and computational challenges associated with these emerging approaches and their perspective

Assessing specialized metabolite diversity in the cosmopolitan plant genus Euphorbia l.

Coevolutionary theory suggests that an arms race between plants and herbivores yields increased plant specialized metabolite diversity and the geographic mosaic theory of coevolution predicts that coevolutionary interactions vary across geographic scales. Consequently, plant specialized metabolite diversity is expected to be highest in coevolutionary hotspots, geographic regions, which exhibit strong reciprocal selection on the interacting species. Despite being well-established theoretical frameworks, technical limitations have precluded rigorous hypothesis testing. Here we aim at understanding how geographic separation over evolutionary time may have impacted chemical differentiation in the cosmopolitan plant genus Euphorbia. We use a combination of state-of-the-art computational mass spectral metabolomics tools together with cell-based high-throughput immunomodulatory testing. Our results show significant differences in specialized metabolite diversity across geographically separated phylogenetic clades. Chemical structural diversity of the highly toxic Euphorbia diterpenoids is significantly reduced in species native to the Americas, compared to Afro-Eurasia. The localization of these compounds to young stems and roots suggest a possible ecological relevance in herbivory defense. This is further supported by reduced immunomodulatory activity in the American subclade as well as herbivore distribution patterns. We conclude that computational mass spectrometric metabolomics coupled with relevant ecological data provide a strong tool for exploring plant specialized metabolite diversity in a chemo-evolutionary framework

Integrative analysis of multimodal mass spectrometry data in MZmine 3

3 Pág.We thank Christopher Jensen and Gauthier Boaglio for their contributions to the MZmine codebase. We thank Jianbo Zhang and Zachary Russ for their donations to MZmine development. The MZmine 3 logo was designed by the Bioinformatics & Research Computing group at the Whitehead Institute for Biomedical Research. T.P. is supported by Czech Science Foundation (GA CR) grant 21-11563M and by the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement 891397. Support for P.C.D. was from US NIH U19 AG063744, P50HD106463, 1U24DK133658 and BBSRC-NSF award 2152526. T.S. acknowledges funding by Deutsche Forschungsgemeinschaft (441958208). M. Wang acknowledges the US Department of Energy Joint Genome Institute ( https://ror.org/04xm1d337 , a DOE Office of Science User Facility) and is supported by the Office of Science of the US Department of Energy operated under subcontract No. 7601660. E.R. and H.H. thank Wen Jiang (HILICON AB) for providing the iHILIC Fusion(+) column for HILIC measurements. M.F., K.D. and S.B. are supported by Deutsche Forschungsgemeinschaft (BO 1910/20). L.-F.N. is supported by the Swiss National Science Foundation (project 189921). D.P. was supported through the Deutsche Forschungsgemeinschaft (German Research Foundation) through the CMFI Cluster of Excellence (EXC-2124 — 390838134 project-ID 1-03.006_0) and the Collaborative Research Center CellMap (TRR 261 - 398967434). J.-K.W. acknowledges the US National Science Foundation (MCB-1818132), the US Department of Agriculture, and the Chan Zuckerberg Initiative. MZmine developers have received support from the European COST Action CA19105 — Pan-European Network in Lipidomics and EpiLipidomics (EpiLipidNET). We acknowledge the support of the Google Summer of Code (GSoC) program, which has funded the development of several MZmine modules through student projects. We thank Adam Tenderholt for introducing MZmine to the GSoC program.Peer reviewe

A community resource for paired genomic and metabolomic data mining

Genomics and metabolomics are widely used to explore specialized metabolite diversity. The Paired Omics Data Platform is a community initiative to systematically document links between metabolome and (meta)genome data, aiding identification of natural product biosynthetic origins and metabolite structures.Peer reviewe

Study of the antiviral activity of Euphorbia extracts from Corsica : Search for new diterpenes of biological interest

Le chikungunya est une maladie transmise par des moustiques du genre Aedes (dont A. albopictus, dit "moustique tigre"). Cette maladie provoque d'intenses fièvres et des douleurs articulaires chroniques fortement invalidantes. Les moustiques potentiellement vecteurs du virus du chikungunya (CHIKV) sont des espèces invasives qui, à la faveur du réchauffement climatique, se sont récemment implantés dans plusieurs régions du monde, dont la région méditerranéenne. Sa présence constitue un terreau favorable à la survenue d'épidémie. A l'heure actuelle, il n'existe ni vaccin, ni traitement médicamenteux efficace. Toutefois, des articles scientifiques ont récemment rapporté que des esters de diterpène isolés du genre Trigonostemon (Euphorbiaceae), avaient une activité inhibitrice de la réplication du CHIKV.Dans le cadre de ces travaux de thèse, des extraits de plantes du genre Euphorbia de Corse ont été étudiés dans le but d'isoler de nouvelles molécules douées d'activité antivirale sur la réplication du CHIKV. En collaboration avec le Dr. P. Leyssen (KU Leuven, Belgique), l'évaluation de l'activité anti-CHIKV de 45 extraits, obtenus à partir de 11 Euphorbiaceae de Corse, a permis de mettre en évidence la forte activité inhibitrice et sélective de des extraits d'espèces du genre Euphorbia in cellulo. L'activité antivirale d'une série de 27 diterpènes de type phorboïde, disponibles commercialement, a également été étudiée. Les résultats ont montré que certains dérivés avaient une forte activité inhibitrice de la réplication du CHIKV, mais aussi sur celle du virus de l'immunodéficience humaine (VIH). Ces études ont permis d'une part, de déduire des relations structure-activité inédites et d'autre part, de soutenir l'hypothèse d'un mécanisme d'action anti-CHIKV impliquant la modulation des protéines kinases C (PKCs) par les phorboïdes. Dans le but de confirmer ou d'infirmer la présence des phorboïdes dans les extraits d'Euphorbia, une première méthode utilisant la chromatographie liquide (LC) haute performance couplée à un spectromètre de masse à trappe d'ions (MSn), a été développée à partir des composés standards. L'application de cette méthodologie a révélé qu'aucun des phorboïdes ciblés n'était présent dans les extraits d'Euphorbia. Ainsi, une seconde procédure LC-MSn a été mise en œuvre afin de détecter - de manière non ciblée - différents types d’esters diterpéniques.Chikungunya fever is caused by an arthropod-borne virus that is associated with massive epidemics and severe morbidity (virus-induced arthralgia, fever, myalgia and rashes). Worldwide expansion of the mosquito vectors, such as Aedes albopictus ("Tiger moquito) is responsible for the spread of Chikungunya virus (CHIKV) throughout the world. A. albopictus has spread throughout Mediterranean areas, which could lead to epidemics outbreaks. Currently, no antiviral drugs or vaccines are available for the treatment or prevention of CHIKV infection. Since ten years, however, recent results showed that diterpene esters from Trignostemon (Euphorbiaceae) possess inhibiting activity of CHIKV replication.With the objective to discover new compounds with antiviral activities, 45 extracts from various plant parts of 11 Euphorbiaceae species native to Corsica were evaluated for selective inhibition of CHIKV replication. In collaboration with Dr. Leyssen (KU Leuven, Belgium), several extracts made from 10 Euphorbia species exhibited significant and selective anti-CHIKV activity in a virus-cell-based assay. The antiviral activities of 29 commercially available phorboïds were studied. Some phorboïds were potent inhibitors of CHIKV and human immunodeficiency virus (VIH) replication. Results allowed drawing new structure-activity relationships, which supported the hypothesis that PKC may be an important target in CHIKV replication. In order to confirm or infirm the presence of phorboïds with anti-CHIKV activity in Euphorbia extracts, a liquid chromatography (LC) coupled to linear ion trap mass spectrometry (MSn) method was developed using standard compounds. Application of this methodology indicated that none anti-CHIKV phorboïds was present in Euphorbia extracts. A second LC-MSn procedure was developed to profile untargeted phorboïdes. Results suggested that numerous other diterpene esters were present in the Euphorbia extracts

An Artificial Intelligence Agent for Navigating Knowledge Graph Experimental Metabolomics Data

International audienceAn experimental knowledge graph (KG) driven framework (10.26434/chemrxiv-2023-sljbt) was recently introduced to facilitate the integration of heterogeneous data types, encompassing both experimental data (mass spectrometry annotation, results from biological screening and fractionation) as well as meta-data available on the Web (such as taxonomies and metabolite databases). Although this KG efficiently encapsulates the different data structures and semantic relationships, retrieving specific information through structured or visually queries or programmatically is not trivial. To unlock the full potential of KGs for scientists of all fields, we designed and implemented a KG-based Artificial Intelligence (AI) agent that can convert natural language questions into programmatic data-mining tasks and generate adapted visualization. By leveraging the potential of emerging Large Language Models (LLMs) to understand semantic relationships encapsulated in KGs and mentioned in the questions, the KGAI-agent autonomously iterates to construct a SPARQL query – the widely-used open standard query language for knowledge graphs – of any submitted natural language question. After retrieving the necessary information from the KG, the KGAI-agent provides a preliminary interpretation of the results in natural language, along with relevant visualizations and statistics. In addition, with follow-up interactions between the LLM and the user, the AI-agent can be expert-guided to refine the initial results and interpretation. Released as an open-source tool, the KGAI-agent acts as a powerful assistant capable of exploring any KG. Accessible in over 50 human languages, it serves to democratize access to semantic databases without requiring bioinformatics expertise. Here we will describe the core principles and components of the KGAI-agent and illustrate how we can query metabolomics information from a KG to discover bioactive metabolites from a collection of 16,000 plant extracts

Metabolites from Microbes Isolated from the Skin of the Panamanian Rocket Frog Colostethus panamansis (Anura: Dendrobatidae)

The Panamanian rocket frog Colostethus panamansis (family Dendrobatidae) has been affected by chytridiomycosis, a deadly disease caused by the fungus Batrachochytrium dendrobatidis (Bd). While there are still uninfected frogs, we set out to isolate microbes from anatomically distinct regions in an effort to create a cultivable resource within Panama for potential drug/agricultural/ecological applications that perhaps could also be used as part of a strategy to protect frogs from infections. To understand if there are specific anatomies that should be explored in future applications of this resource, we mapped skin-associated bacteria of C. panamansis and their metabolite production potential by mass spectrometry on a 3D model. Our results indicate that five bacterial families (Enterobacteriaceae, Comamonadaceae, Aeromonadaceae, Staphylococcaceae and Pseudomonadaceae) dominate the cultivable microbes from the skin of C. panamansis. The combination of microbial classification and molecular analysis in relation to the anti-Bd inhibitory databases reveals the resource has future potential for amphibian conservation

LC-MS(2)-Based dereplication of Euphorbia extracts with anti-Chikungunya virus activity

Recently, phorbol esters from Euphorbiaceae have been shown to elicit potent and selective antiviral activity on the replication of Chikungunya virus (CHIKV) in cell culture. With the objective to found new compounds with anti-CHIKV activities, 45 extracts from various plant parts of 11 Mediterranean Euphorbia and one Mercurialis species were evaluated for selective inhibition of CHIKV replication. All EtOAc extracts, especially those prepared from latex, exhibited significant and selective antiviral activity in a Chikungunya virus-cell-based assay. An LC-MS(2) dereplication method was then developed to investigate whether known diterpenoids with anti-CHIKV activity, such as the potent anti-CHIKV 12-O-tetradecanoylphorbol-13-acetate (TPA), phorbol-12,13-didecanoate, and prostratin as well as 24 other commercially available diterpenoids of tigliane-, ingenane-, and daphnane-type for which the anti-CHIKV activity have been established in advance (Nothias-Scaglia et al. 2015), were present in the Euphorbia extracts. Only ingenol-3-mebutate, 13-O-isobutyryl-12-deoxyphorbol-20-acetate, and ingenol-3,20-dibenzoate, all exhibiting weak anti-CHIKV activities, were detected in the EtOAc extracts of Euphorbia peplus, Euphorbia segetalis ssp. pinea, and Euphorbia pithyusa ssp. pithyusa. Given the potent anti-CHIKV activities of these Euphorbia extracts, the present study suggested that their antiviral activities are probably due to untargeted diterpenoids.publisher: Elsevier articletitle: LC-MS2-Based dereplication of Euphorbia extracts with anti-Chikungunya virus activity journaltitle: Fitoterapia articlelink: http://dx.doi.org/10.1016/j.fitote.2015.06.021 content_type: article copyright: Copyright © 2015 Elsevier B.V. All rights reserved.status: publishe