Publications by authors named "Soizic Prado"

47 Publications

A community perspective on the concept of marine holobionts: current status, challenges, and future directions.

PeerJ 2021 25;9:e10911. Epub 2021 Feb 25.

Integrative Biology of Marine Models (LBI2M), Station Biologique de Roscoff, Sorbonne Université, CNRS, Roscoff, France.

Host-microbe interactions play crucial roles in marine ecosystems. However, we still have very little understanding of the mechanisms that govern these relationships, the evolutionary processes that shape them, and their ecological consequences. The holobiont concept is a renewed paradigm in biology that can help to describe and understand these complex systems. It posits that a host and its associated microbiota with which it interacts, form a holobiont, and have to be studied together as a coherent biological and functional unit to understand its biology, ecology, and evolution. Here we discuss critical concepts and opportunities in marine holobiont research and identify key challenges in the field. We highlight the potential economic, sociological, and environmental impacts of the holobiont concept in marine biological, evolutionary, and environmental sciences. Given the connectivity and the unexplored biodiversity specific to marine ecosystems, a deeper understanding of such complex systems requires further technological and conceptual advances, e.g., the development of controlled experimental model systems for holobionts from all major lineages and the modeling of (info)chemical-mediated interactions between organisms. Here we propose that one significant challenge is to bridge cross-disciplinary research on tractable model systems in order to address key ecological and evolutionary questions. This first step is crucial to decipher the main drivers of the dynamics and evolution of holobionts and to account for the holobiont concept in applied areas, such as the conservation, management, and exploitation of marine ecosystems and resources, where practical solutions to predict and mitigate the impact of human activities are more important than ever.
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http://dx.doi.org/10.7717/peerj.10911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916533PMC
February 2021

Cytotoxic constituents from the wheat plant pathogen SN15.

Nat Prod Res 2021 Feb 19:1-8. Epub 2021 Feb 19.

Unité Molécules de Communication et Adaptation des Micro-organismes, UMR 7245, Muséum National d'Histoire Naturelle, Paris, France.

Microbial natural products are continuing to be a promising platform for future drug lead discover. As a part of our ongoing research program on fungal natural product, herein we report metabolites isolated from the fungus SN15 a pathogen of wheat and related cereals. Its chemical investigation led to the purification of new isoleucinic acid derivatives (-) along with the procuramine (). Their structures were determined based on extensive NMR and the relative configuration by comparison of experimental and predicted NMR chemical shifts. All compounds were evaluated for their cytotoxic activity against a panel of human cell lines and some displayed specific feature towards cancer cells compared to normal immortalised fibroblasts.
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http://dx.doi.org/10.1080/14786419.2021.1877702DOI Listing
February 2021

Pentadecaibins I-V: 15-Residue Peptaibols Produced by a Marine-Derived sp. of the Clade.

J Nat Prod 2021 Apr 18;84(4):1271-1282. Epub 2021 Feb 18.

Université de Nantes, MMS - EA2160, 44000 Nantes, France.

In the course of investigations on peptaibol chemodiversity from marine-derived spp., five new 15-residue peptaibols named pentadecaibins I-V (-) were isolated from the solid culture of the strain sp. MMS1255 belonging to the species complex. Phylogenetic analyses allowed precise positioning of the strain close to lineage inside the clade. Peptaibol sequences were elucidated on the basis of their MS/MS fragmentation and extensive 2D NMR experiments. Amino acid configurations were determined by Marfey's analyses. The pentadecaibins are based on the sequences Ac-Aib-Gly-Ala-Leu-Aib/Iva-Gln-Aib/Iva-Val/Leu-Aib-Ala-Aib-Aib-Aib-Gln-Pheol. Characteristic of the pentadecaibin sequences is the lack of the Aib-Pro motif commonly present in peptaibols produced by spp. Genome sequencing of sp. MMS1255 allowed the detection of a 15-module NRPS-encoding gene closely associated with pentadecaibin biosynthesis. Pentadecaibins were assessed for their potential antiproliferative and antimicrobial activities.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01355DOI Listing
April 2021

Biosynthesis of azaphilones: a review.

Nat Prod Rep 2021 Feb 2. Epub 2021 Feb 2.

Normandie Univ., CNRS, UNIROUEN, INSA Rouen, COBRA (UMR 6014 & FR 3038), 76000 Rouen, France.

Covering up to 2020Azaphilones are fungal polyketide pigments bearing a highly oxygenated pyranoquinone bicyclic core; they are receiving a great deal of increasing research interest for their applications in the agroalimentary, dyeing, cosmetic, printing and pharmaceutical industries. Their biosynthetic pathways are not fully elucidated; however, thanks to recent genomic approaches combined with the increasing genome sequencing of fungi, some of these pathways have been recently unveiled. This is the first review on the biosynthesis of azaphilonoids adressed from a genomic point of view.
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http://dx.doi.org/10.1039/d0np00080aDOI Listing
February 2021

Laminariales Host Does Impact Lipid Temperature Trajectories of the Fungal Endophyte (Sutherland.).

Mar Drugs 2020 Jul 22;18(8). Epub 2020 Jul 22.

Laboratoire de Biologie des Organismes et Ecosystèmes Aquatiques (BOREA), Muséum National d'Histoire Naturelle, IRD, SU, CNRS, UA, UCN, Station Marine de Concarneau, FR-29900 Concarneau, France.

Kelps are colonized by a wide range of microbial symbionts. Among them, endophytic fungi remain poorly studied, but recent studies evidenced yet their high diversity and their central role in algal defense against various pathogens. Thus, studying the metabolic expressions of kelp endophytes under different conditions is important to have a better understanding of their impacts on host performance. In this context, fatty acid composition is essential to a given algae fitness and of interest to food web studies either to measure its nutritional quality or to infer about its contribution to consumers diets. In the present study, , a fungal endophyte was isolated from (L.) and (Hudson.) and its fatty acid composition was assessed at increasing salinity and temperature conditions. Results showed that fungal composition in terms of fatty acids displayed algal-dependent trajectories in response to temperature increase. This highlights that C18 unsaturated fatty acids are key components in the host-dependant acclimation of to salinity and temperature changes.
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http://dx.doi.org/10.3390/md18080379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460085PMC
July 2020

Molecular crosstalk between the endophyte Paraconiothyrium variabile and the phytopathogen Fusarium oxysporum - Modulation of lipoxygenase activity and beauvericin production during the interaction.

Fungal Genet Biol 2020 06 6;139:103383. Epub 2020 Apr 6.

Muséum National d'Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes, UMR 7245, CP 54, 57 Rue Cuvier, 75005 Paris, France; Sorbonne Université, Faculté des Sciences et Ingénierie, UFR 927, F-75005 Paris, France. Electronic address:

Plants comprise many asymptomatic fungal endophytes with potential roles of plant protection against abiotic and biotic stresses. Endophytes communicate with their host plant, with other endophytes and with invading pathogens but their language remains largely unknown. This work aims at understanding the chemical communication and physiological interactions between the fungal endophyte Paraconiothyrium variabile and the phytopathogen Fusarium oxysporum. Oxylipins, common means of communication, such as 13-hydroperoxy-9,11-octadecadienoic acid (13-HPODE), had been shown in our earlier studies to be overproduced during dual culture between the two fungal antagonists. On the other hand, the mycotoxin beauvericin was reduced in the interaction zone. The present work addresses the mechanisms underlying these changes. Hydroperoxy oxylipins are produced by lipoxygenases and P. variabile contains two lipoxygenase genes (pvlox1 and pvlox2), whereas pvlox2, but not pvlox1, is specifically up regulated during the interaction and none of the F. oxysporum lox genes vary. Heterologous expression of pvlox2 in yeast shows that the corresponding enzyme PVLOX2 produces 13-HPODE and, therefore, is most likely at the origin of the overproduced 13-HPODE during the interaction. Compellingly, beauvericin synthase gene beas expression is induced and beauvericin amounts increase in F. oxysporum mycelium when in contact with P. variabile. 13-HPODE, however, does not affect beas gene expression. Beauvericin, indeed, inhibits P. variabile growth, which counteracts and biotransforms the mycotoxin leading to reduced amounts in the interaction zone which allows further expansion of the endophyte. In order to study the interaction between the protagonists in planta, we set up an in vitro tripartite interaction assay, including the model plant Arabidopsis thaliana. F. oxysporum rapidly kills A. thaliana plants, whereas P. variabile provides up to 85% reduction of plant death if present before pathogen attack. Future studies will shed light on the protection mechanisms and the role of oxylipins and beauvericin degradation herein with the long-term aim of using endophytes in plant protection.
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http://dx.doi.org/10.1016/j.fgb.2020.103383DOI Listing
June 2020

Secondary Metabolites from the Culture of the Marine-derived Fungus PC 362H and Evaluation of the Anticancer Activity of Its Metabolite Hyalodendrin.

Mar Drugs 2020 Apr 3;18(4). Epub 2020 Apr 3.

Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France.

High-throughput screening assays have been designed to identify compounds capable of inhibiting phenotypes involved in cancer aggressiveness. However, most studies used commercially available chemical libraries. This prompted us to explore natural products isolated from marine-derived fungi as a new source of molecules. In this study, we established a chemical library from 99 strains corresponding to 45 molecular operational taxonomic units and evaluated their anticancer activity against the MCF7 epithelial cancer cell line and its invasive stem cell-like MCF7-Sh-WISP2 counterpart. We identified the marine fungal PC 362H strain, isolated from the brown alga (PC), as one of the most promising fungi which produce active compounds. Further chemical and biological characterizations of the culture of the PC 362H strain identified (-)-hyalodendrin as the active secondary metabolite responsible for the cytotoxic activity of the crude extract. The antitumor activity of (-)-hyalodendrin was not only limited to the MCF7 cell lines, but also prominent on cancer cells with invasive phenotypes including colorectal cancer cells resistant to chemotherapy. Further investigations showed that treatment of MCF7-Sh-WISP2 cells with (-)-hyalodendrin induced changes in the phosphorylation status of p53 and altered expression of HSP60, HSP70 and PRAS40 proteins. Altogether, our study reveals that this uninvestigated marine fungal crude extract possesses a strong therapeutic potential against tumor cells with aggressive phenotypes and confirms that members of the epidithiodioxopiperazines are interesting fungal toxins with anticancer activities.
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http://dx.doi.org/10.3390/md18040191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230232PMC
April 2020

Cytotoxic and Anti-Inflammatory Effects of -Kaurane Derivatives Isolated from the Alpine Plant .

Molecules 2020 Jan 29;25(3). Epub 2020 Jan 29.

Laboratoire de Chimie-Toxicologie Analytique et Cellulaire (C-TAC) UMR CNRS 8038 CiTCoM Université Paris-Descartes, 4, avenue de l'Observatoire, 75006 Paris, France.

This paper reports the isolation and structural characterization of four new -kaurane derivatives from the Lamiaceae plant . Planar structures and relative configurations were determined using both mass spectrometry and nuclear magnetic resonance (1D and 2D). Absolute configurations were determined by comparing experimental and theoretical electronic circular dichroism spectra. The cytotoxic and microbial activities of all new compounds were tested. Compounds that were non-cytotoxic were further evaluated for anti-inflammatory activity.
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http://dx.doi.org/10.3390/molecules25030589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037520PMC
January 2020

Bacterial-Fungal Interactions in the Kelp Endomicrobiota Drive Autoinducer-2 Quorum Sensing.

Front Microbiol 2019 31;10:1693. Epub 2019 Jul 31.

Unité Molécules de Communication et Adaptation des Microorganismes (MCAM), Muséum National d'Histoire Naturelle (MNHN), Centre National de la Recherche Scientifique (CNRS), CP 54, Paris, France.

Brown macroalgae are an essential component of temperate coastal ecosystems and a growing economic sector. They harbor diverse microbial communities that regulate algal development and health. This algal holobiont is dynamic and achieves equilibrium a complex network of microbial and host interactions. We now report that bacterial and fungal endophytes associated with four brown algae (, , , and produce metabolites that interfere with bacterial autoinducer-2 quorum sensing, a signaling system implicated in virulence and host colonization. Additionally, we performed co-culture experiments combined to a metabolomic approach and demonstrated that microbial interactions influence production of metabolites, including metabolites involved in quorum sensing. Collectively, the data highlight autoinducer-2 quorum sensing as a key metabolite in the complex network of interactions within the algal holobiont.
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http://dx.doi.org/10.3389/fmicb.2019.01693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685064PMC
July 2019

Highly oxygenated isoprenylated cyclohexanoids from the fungus Parastagonospora nodorum SN15.

Phytochemistry 2019 Oct 11;166:112056. Epub 2019 Jul 11.

Muséum National d'Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes, UMR 7245, CP 54, 57 Rue Cuvier, 75005, Paris, France. Electronic address:

The chemical investigation of the wheat plant pathogen Parastagonospora nodorum SN15 led to the purification of seven highly oxygenated acetylenic cyclohexanoids named stagonosporynes A-G. Their structures were determined on the basis of extensive NMR and the relative and absolute configurations by an array of computational methods including simulation of NOESY spectrum and electronic circular dichroism (ECD). All compounds were evaluated for their herbicidal activity and stagonosporyne G displayed the most significant herbicidal activity.
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http://dx.doi.org/10.1016/j.phytochem.2019.112056DOI Listing
October 2019

Chemically-Mediated Interactions Between Macroalgae, Their Fungal Endophytes, and Protistan Pathogens.

Front Microbiol 2018 21;9:3161. Epub 2018 Dec 21.

Muséum National d'Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes, UMR 7245, CP 54, Paris, France.

Filamentous fungi asymptomatically colonize the inner tissues of macroalgae, yet their ecological roles remain largely underexplored. Here, we tested if metabolites produced by fungal endophytes might protect their host against a phylogenetically broad spectrum of protistan pathogens. Accordingly, the cultivable fungal endophytes of four brown algal species were isolated and identified based on LSU and SSU sequencing. The fungal metabolomes were tested for their ability to reduce the infection by protistan pathogens in the algal model . The most active metabolomes effective against the oomycetes and , and the phytomixid were further characterized chemically. Several pyrenocines isolated from sp. AN596H efficiently inhibited the infection by all abovementioned pathogens. Strikingly, these compounds also inhibited the infection of () against its two most devastating oomycete pathogens, , and . We thus demonstrate that fungal endophytes associated with brown algae produce bioactive metabolites which might confer protection against pathogen infection. These results highlight the potential of metabolites to finely-tune the outcome of molecular interactions between algae, their endophytes, and protistan pathogens. This also provide proof-of-concept toward the applicability of such metabolites in marine aquaculture to control otherwise untreatable diseases.
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http://dx.doi.org/10.3389/fmicb.2018.03161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309705PMC
December 2018

An Integrative Approach to Decipher the Chemical Antagonism between the Competing Endophytes Paraconiothyrium variabile and Bacillus subtilis.

J Nat Prod 2017 11 15;80(11):2863-2873. Epub 2017 Nov 15.

Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245), Sorbonne Université, Muséum National d'Histoire Naturelle, CNRS , CP 54, 57 rue Cuvier, 75005 Paris, France.

An integrative approach combining traditional natural products chemistry, molecular networking, and mass spectrometry imaging has been undertaken to decipher the molecular dialogue between the fungus Paraconiothyrium variabile and the bacterium Bacillus subtilis, which were isolated as endophytes from the conifer Cephalotaxus harringtonia and are characterized by a strong and mutual antibiosis. From this study, we highlight that bacterial surfactins and a fungal tetronic acid are involved in such competition and that the fungus is able to hydrolyze surfactins to fight against the bacterial partner.
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http://dx.doi.org/10.1021/acs.jnatprod.6b01185DOI Listing
November 2017

A Reactive Eremophilane and Its Antibacterial 2(1H)-Naphthalenone Rearrangement Product, Witnesses of a Microbial Chemical Warfare.

Org Lett 2017 08 24;19(15):4038-4041. Epub 2017 Jul 24.

Muséum National d'Histoire Naturelle , CNRS (UMR 7245 MCAM), Sorbonne Universités, 57 rue Cuvier (CP 54), 75005 Paris, France.

Two sesquiterpenes, 4-epi-microsphaeropsisin (1) and a dihydrofurano-2(1H)-naphthalenone (variabilone, 2) which represents a new skeleton, were isolated from endophytic fungus Paraconiothyrium variabile. Reactivity studies showed that eremophilane 1 is a precursor of 2 through acid-promoted methyl 1,2-migration and aromatization. An electrophilic intermediate of this transformation was intercepted by N-acetylcysteamine, a biomimetic nucleophile. Only compound 2 was antibacterial against endophytic bacterium Bacillus subtilis (coisolated with P. variabile), suggesting a role in the microbial competition in plants.
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http://dx.doi.org/10.1021/acs.orglett.7b01788DOI Listing
August 2017

Antimicrobial Oligophenalenone Dimers from the Soil Fungus Talaromyces stipitatus.

J Nat Prod 2016 Dec 14;79(12):2991-2996. Epub 2016 Dec 14.

Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245), Sorbonne Université, Muséum National d'Histoire Naturelle , CNRS, CP 54, 57 Rue Cuvier, 75005 Paris, France.

New polyketide-derived oligophenalenone dimers, 9a-epi-bacillisporin E (1) and bacillisporins F-H (2-5), along with the known bacillisporin A (6), were isolated from the fungus Talaromyces stipitatus. Their structures and absolute configurations were determined on the basis of spectroscopic analyses, electronic circular dichroism, and GIAO NMR shift calculation followed by DP4 analysis. The antimicrobial activity of these compounds was evaluated against a panel of human pathogenic bacteria. Among them, bacillisporin H (5) exhibited antimicrobial activity together with modest cytotoxicity against HeLa cells.
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http://dx.doi.org/10.1021/acs.jnatprod.6b00458DOI Listing
December 2016

Genotype- or Phenotype-Targeting Anticancer Therapies? Lessons from Tumor Evolutionary Biology.

Curr Pharm Des 2016 ;22(44):6625-6644

Sorbonne Universites, UPMC Univ Paris 06, INSERM, Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), UMR_S 938, F-75012 Paris, France.

Despite the efficacy of most cancer therapies, drug resistance remains a major problem in the clinic. The eradication of the entire tumor and the cure of the patient by chemotherapy alone are rare, in particular for advanced disease. From an evolutionary perspective, the selective pressure exerted by chemotherapy leads to the emergence of resistant clones where resistance can be associated with many different functional mechanisms at the single cell level or can involve changes in the tumor micro-environment. In the last decade, tumor genomics has contributed to the improvement of our understanding of tumorigenesis and has led to the identification of numerous cellular targets for the development of novel therapies. However, since tumors are by nature extremely heterogeneous, the drug efficacy and economical sustainability of this approach is now debatable. Importantly, tumor cell heterogeneity depends not only on genetic modifications but also on non-genetic processes involving either stochastic events or epigenetic modifications making genetic biomarkers of uncertain utility. In this review, we wish to highlight how evolutionary biology can impact our understanding of carcinogenesis and resistance to therapies. We will discuss new approaches based on applied ecology and evolution dynamics that can be used to convert the cancer into a chronic disease where the drugs would control tumor growth. Finally, we will discuss the way metabolic dysfunction or phenotypic changes can help developing new delivery systems or phenotypetargeted drugs and how exploring new sources of active compounds can conduct to the development of drugs with original mechanisms of action.
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http://dx.doi.org/10.2174/1381612822666160831114002DOI Listing
March 2018

Automated Detection of Natural Halogenated Compounds from LC-MS Profiles-Application to the Isolation of Bioactive Chlorinated Compounds from Marine-Derived Fungi.

Anal Chem 2016 09 2;88(18):9143-50. Epub 2016 Sep 2.

University of Nantes , Faculty of Pharmacy, MMS-EA2160, 44035 Nantes, France.

A collection of culture extracts obtained from several marine-derived fungal strains collected on the French Atlantic coast was investigated by high performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) in order to prospect for halogenated compounds and to identify potentially new ones. To achieve a fast, automated, and efficient data analysis, a bioinformatics tool named MeHaloCoA (Marine Halogenated Compound Analysis) was developed and included into R. After extraction of all the peaks from the metabolic fingerprints and their associated mass spectra, a mathematical filter based on mass isotopic profiles allowed the selective detection of halogenated (Cl and Br) molecules. Integrating MeHaloCoA into a dereplication approach allowed the identification of known and new halogenated compounds in a competitive amount of time. Subsequent targeted purification led to the isolation of several chlorinated metabolites, including two new natural products with bioactive potential, griseophenone I and chlorogriseofulvin, from a marine-derived Penicillium canescens strain.
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http://dx.doi.org/10.1021/acs.analchem.6b02128DOI Listing
September 2016

Talaroketals A and B, unusual bis(oxaphenalenone) spiro and fused ketals from the soil fungus Talaromyces stipitatus ATCC 10500.

Org Biomol Chem 2016 Mar;14(9):2691-7

Sorbonne Universités, Muséum national d'Histoire naturelle, CNRS, Laboratoire Molécules de Communication et Adaptation des Microorganismes (MCAM), UMR 7245 CNRS-MNHN, CP 54, 57 rue Cuvier, 75005 Paris, France.

Two novel oxaphenalenone dimers, talaroketals A () and B (), were isolated from the soil fungus Talaromyces stipitatus. Their structures and absolute configurations were determined on the basis of spectroscopic analyses, X-ray diffraction experiments and electronic circular dichroism. Compound () features a rare benzannulated 5,6-spiroketal ring system within the dimeric bis(oxaphenalenone) skeleton while the parent compound () harbors a fused bicyclic furano-pyran moiety. These two compounds may biogenetically result from the reaction of duclauxin with a dihydrofuran derivative of botryodiplodin. Additionally, talaroketals A () and B () display modest antimicrobial activity against Staphylococcus aureus.
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http://dx.doi.org/10.1039/c5ob02657aDOI Listing
March 2016

Unexpected talaroenamine derivatives and an undescribed polyester from the fungus Talaromyces stipitatus ATCC10500.

Phytochemistry 2015 Nov 18;119:70-5. Epub 2015 Sep 18.

Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS/MNHN, Muséum National d'Histoire Naturelle, 57 rue Cuvier (CP54), 75231 Paris Cedex 05, France. Electronic address:

Chemical investigation of the fungus Talaromyces stipitatus ATCC 10500, whose genome has been sequenced, led to the isolation of four undescribed talaroenamines B-E along with the known talaroenamine A. Their structures were elucidated on the basis of spectroscopic studies including mass spectrometry, extensive 2D NMR and electronic circular dichroism (ECD). Interestingly, talaroenamine A had previously been isolated from the strain of T. stipitatus Δtrop C, a strain knocked out for the gene encoding a non-heme Fe(II)-dependent dioxygenase catalyzing the oxidative ring expansion leading to the tropolone, but never from a wild-type strain. All talaroenamines were evaluated for their antiplasmodial activity and Talaroenamine D exhibited the best inhibition against the chloroquine-resistant Plasmodium falciparum (FcB1 strain) without noticeable toxicity on HeLa and preadipose cell lines. In the course of the chemical investigation of T. stipitatus, an undescribed polyester was also isolated and its absolute configuration was determined by hydrolysis and transesterification followed by gas chromatography on chiral column.
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http://dx.doi.org/10.1016/j.phytochem.2015.09.002DOI Listing
November 2015

The fungal leaf endophyte Paraconiothyrium variabile specifically metabolizes the host-plant metabolome for its own benefit.

Phytochemistry 2014 Dec 21;108:95-101. Epub 2014 Oct 21.

Molécules de Communication et Adaptation des Microorganismes (MCAM), UMR 7245 CNRS/Muséum National d'Histoire Naturelle, Paris, France. Electronic address:

Fungal endophytes live inside plant tissues and some have been found to provide benefits to their host. Nevertheless, their ecological impact is not adequately understood. Considering the fact that endophytes are continuously interacting with their hosts, it is conceivable that both partners have substantial influence on each other's metabolic processes. In this context, we have investigated the action of the endophytic fungus Paraconiothyrium variabile, isolated from the leaves of Cephalotaxus harringtonia, on the secondary metabolome of the host-plant. The alteration of the leaf compounds by the fungus was monitored through metabolomic approaches followed by structural characterization of the altered products. Out of more than a thousand molecules present in the crude extract of the plant leaf, we have observed a specific biotransformation of glycosylated flavonoids by the endophyte. In all cases it led to the production of the corresponding aglycone via deglycosylation. The deglycosylated flavonoids turned out to display significant beneficial effects on the hyphal growth of germinated spores. Our finding, along with the known allelopathic role of flavonoids, illustrates the chemical cooperation underlying the mutualistic relationship between the plant and the endophyte.
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http://dx.doi.org/10.1016/j.phytochem.2014.09.021DOI Listing
December 2014

Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues.

Beilstein J Org Chem 2013 31;9:1551-8. Epub 2013 Jul 31.

Muséum National d'Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, France.

Aurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad-Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure-activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization.
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http://dx.doi.org/10.3762/bjoc.9.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740496PMC
August 2013

Geographic locality greatly influences fungal endophyte communities in Cephalotaxus harringtonia.

Fungal Biol 2013 Feb 8;117(2):124-36. Epub 2013 Jan 8.

Origine, Structure et Evolution de la Biodiversité, UMR 7205 CNRS/MNHN, Muséum National d'Histoire Naturelle, Paris, France.

Although endophytes of conifers have been extensively studied, few data are available on Cephalotaxaceae. We examined foliar and stem endophytes of Cephalotaxus harringtonia, within its natural range in Japan and outside its natural range in France to study the effect of geography on endophyte community composition. In Japan, rapidly growing endophytes were dominant and may have masked the real diversity, in comparison to France where most endophytes were growing slowly. Analyses of ITS rDNA revealed 104 different Blast Groups among 554 isolates. Almost no overlap between endophyte assemblages of C. harringtonia from the two countries was observed. It seems that Japanese C. harringtonia trees, which should be well adapted to their native site, would host a specific, endemic endophyte community, while trees that have been introduced recently to a foreign site, in France, should have captured existing cosmopolitan and more generalist taxa. In Japan the majority of xylariaceous taxa, which dominated the communities, were unknown and, although closely related to Asian taxa, may be new to science. Dothideomycetes were more prevalent in France. Locally, urban environment, particularly in Japan, may have introduced some perturbations in the native endophyte community of C. harringtonia, with an abundance of generalist fungi such as Nigrospora and Colletotrichum.
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http://dx.doi.org/10.1016/j.funbio.2012.12.005DOI Listing
February 2013

Nukuhivensiums, indolo[2,3-a]quinoliziniums from the Marquesan plant Rauvolfia nukuhivensis.

Molecules 2012 Oct 12;17(10):12015-22. Epub 2012 Oct 12.

EIMS Laboratory UMR 241 EIO, University of French Polynesia, 98702 Faa'a, Tahiti, French Polynesia.

The first phytochemical inspection of the Marquesan endemic plant Rauvolfia nukuhivensis led to the isolation and structure characterization of two new indolo[2,3-a]quinolizinium derivatives named nukuhivensium and N₁₂-methyl-nukuhivensium. They feature an aromatic indolo[2,3-a]quinolizinium core, substituted at C-2 by a n-propyl group, which is unusual in this family of alkaloid derivatives. The structure elucidation was performed on the basis of NMR spectroscopy and especially by interpretation of 2D HMBC correlations. A biosynthetic pathway is proposed on the basis of known enzymatic transformations for this family of natural products. These compounds exhibited low antimicrobial activities.
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http://dx.doi.org/10.3390/molecules171012015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268674PMC
October 2012

Chemical communication between the endophytic fungus Paraconiothyrium variabile and the phytopathogen Fusarium oxysporum.

PLoS One 2012 15;7(10):e47313. Epub 2012 Oct 15.

UMR 7245, MCAM, MNHN CNRS, Muséum National d'Histoire Naturelle, Paris, France.

Paraconiothyrium variabile, one of the specific endophytic fungi isolated from the host plant Cephalotaxus harringtonia, possesses the faculty to inhibit the growth of common phytopathogens, thus suggesting a role in its host protection. A strong antagonism between the endophyte P. variabile and Fusarium oxysporum was observed and studied using optic and electronic microscopies. A disorganization of the mycelium of F. oxysporum was thus noticed. Interestingly, the biological effect of the main secondary metabolites isolated from P. variabile against F. oxysporum did not account for this strong antagonism. However, a metabolomic approach of pure fungal strains and confrontation zones using the data analysis tool XCMS were analyzed and pointed out a competition-induced metabolite production by the endophyte in the presence of the phytopathogen. Subsequent MS/MS fragmentations permitted to identify one of the induced metabolites as 13-oxo-9,11-octadecadienoic acid and highlighted a negative modulation of the biosynthesis of beauvericin, one of the most potent mycotoxin of F. oxysporum, during the competition with the endophyte.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047313PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471838PMC
July 2013

Synthesis and antimicrobial activities of some sulphur containing chromene derivatives.

Nat Prod Commun 2012 Jul;7(7):891-4

Department of Pharmacognosy, Faculty of Pharmacy, Istanbul University, 34116 Istanbul, Turkey.

A series of 3,3-dimethyl-3Hbenzothieno[3,2-f][1]-benzopyran analogues modified at the pyran 1,2-double bond were synthesized. The corresponding dihydro and (+/-)-cis-diol derivatives were converted into diacetate and cyclic carbonate upon acylation. The title compounds were characterized by spectroscopic analysis and screened for their antimicrobial activity in vitro.
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July 2012

Photodegradation of the Mycobacterium ulcerans toxin, mycolactones: considerations for handling and storage.

PLoS One 2012 13;7(4):e33600. Epub 2012 Apr 13.

Unité Inserm U892, Équipe 15, Nantes-Angers, France.

Background: Mycolactones are toxins secreted by M. ulcerans, the etiological agent of Buruli ulcer. These toxins, which are the main virulence factors of the bacilli, are responsible for skin lesions. Considering their specificity for M. ulcerans and their presence in skin lesions even at early stages, mycolactones are promising candidates for the development of a diagnostic tool for M. ulcerans infection. Stability of purified mycolactones towards light and heat has not yet been investigated, despite the importance of such parameters in the selection of strategies for a diagnosis tool development. In this context, the effects of UV, light and temperature on mycolactone stability and biological activity were studied.

Methodology/principal Findings: To investigate the effect of these physical parameters, mycolactones were exposed to different wavelengths in several solvents and temperatures. Structural changes and biological activity were monitored. Whilst high temperature had no effect on mycolactones, UV irradiation (UV-A, UV-B and UV-C) and sunlight exposure caused a considerable degradation, as revealed by LC-MS and NMR analysis, correlated with a loss of biological activity. Moreover, effect of UVs on mycolactone caused a photodegradation rather than a phototransformation due to the identification of degradation product.

Conclusion/significance: This study demonstrates the high sensitivity of mycolactones to UVs as such it defines instructions for storage and handling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033600PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326021PMC
August 2012

Guaiane sesquiterpenes from Biscogniauxia nummularia featuring potent antigerminative activity.

J Nat Prod 2012 Apr 9;75(4):798-801. Epub 2012 Apr 9.

Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS/MNHN, Muséum National d'Histoire Naturelle, 57 Rue Cuvier (CP54), 75231 Paris Cedex 05, France.

Xylaranone, a previously unreported guaiane sesquiterpene along with the known terpenoid xylaranol B and the two mellein derivatives 3,5-dimethyl-8-methoxy-3,4-dihydroisocoumarin and 3,5-dimethyl-8-hydroxy-3,4-dihydroisocoumarin were isolated from Biscogniauxia nummularia. Pogostol was also isolated from this fungus, and in light of our spectroscopic data, its structure was revised and corrected. This fungus, which was isolated as an endophyte from the plum yew Cephalotaxus harringtonia, is also suspected of being a pathogen. Interestingly, we report here the potent antigerminative activity of xylaranone and xylaranol B against seeds of Raphanus sativus at concentrations comparable to glyphosate, a commonly used herbicide. This effect suggests a role for these metabolites in the latent fungal pathogenesis of B. nummularia.
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http://dx.doi.org/10.1021/np2009913DOI Listing
April 2012

Unprecedented occurrence of isoaspartic acid in a plant cyclopeptide.

Org Lett 2012 Jan 5;14(2):576-9. Epub 2012 Jan 5.

Molécules de Communication et Adaptation des Micro-Organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle, 63 rue Buffon 75005 Paris, France.

Three structurally related cycloheptapeptides, cyclocitropsides A-C, have been isolated from a MeOH extract of the root bark of Citropsis articulata, a medicinal plant in Uganda. Their sequences were elucidated on the basis of their MS/MS fragmentation, extensive 2D-NMR, chemical degradation, and biochemical modifications. Surprisingly, the sequence of cyclocitropside C differed from that of cyclocitropside B only by an Asp(5)/isoAsp(5) substitution. This is the first report of an isoAsp residue in a plant cyclic peptide.
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http://dx.doi.org/10.1021/ol203190fDOI Listing
January 2012

Structure and in vitro antiparasitic activity of constituents of Citropsis articulata root bark.

J Nat Prod 2011 Oct 10;74(10):2286-9. Epub 2011 Oct 10.

Molécules de Communication et Adaptation des Micro-Organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle, 63 rue Buffon 75005 Paris, France.

From the results of an ethnomedicinal investigation of plants from Uganda with antimalarial activity, Citropsis articulata was selected because of the antiplasmodial effect of an ethyl acetate extract of its root bark. Thus, from the cyclohexane, ethyl acetate, and methanol extracts, two new heterocyclic compounds, omubioside (1) and katimborine (2), were isolated in addition to five known coumarins (rutarin (3), seselin (4), suberosin (5), demethylsuberosin (6), and haploperoside (7)), two known alkaloids (5-hydroxynoracronycine (8) and 1,5-dihydroxy-2,3-dimethoxy-10-methyl-9-acridone (9)), trigonelline (10), and the limonoid 7α-obacunyl acetate (11). The best growth inhibitors of Plasmodium falciparum were alkaloids 8 and 9, with IC50 values of 0.9 and 3.0 μg/mL.
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http://dx.doi.org/10.1021/np2004825DOI Listing
October 2011

Furfuran lignans and a flavone from Artemisia gorgonum Webb and their in vitro activity against Plasmodium falciparum.

J Ethnopharmacol 2011 Nov 29;138(2):637-40. Epub 2011 Sep 29.

Université de Nice-Sophia Antipolis, Laboratoire de Chimie des Molécules Bioactives et des Arômes, UMR 6001 CNRS, Faculté des Sciences, 28 Avenue Valrose, 06108 Nice Cedex 2, France.

The chemical composition of the aerial parts of the Cape Verdean endemic shrub Artemisia gorgonum Webb (Asteraceae) was careful investigated, which led to the isolation and identification of six known furfuran lignans: eudesmin (1), magnolin (2), epimagnolin A (3), aschantin (4), kobusin (5), sesamin (6) and a flavone: artemetin (7). Compounds 1-7 were evaluated in vitro for their cytotoxicity in a screening panel consisting of various mammalian tumor cell lines, for their antimalarial activity against chloroquine-resistant Plasmodium falciparum (FcB1 strain) and for their cytotoxicity against murine normal cells (CFU-GM). While no promising cytotoxicity against human tumor cells were noticed, marginal potency and selectivity was found for compounds 1-5 against murine colon 38. Besides, compounds 2-7 showed mild antiplasmodial activities, 6 and 7 being the most active compounds (IC(50) 3.37 and 3.50 μg/ml respectively) without noticeable toxicity on mammalian normal cells. This is the first report of antiplasmodial activity for furfuran lignans and the first isolation of 1-7 from Artemisia gorgonum.
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http://dx.doi.org/10.1016/j.jep.2011.09.039DOI Listing
November 2011

Insecticidal cyclodepsipeptides from Beauveria felina.

J Nat Prod 2011 Apr 25;74(4):825-30. Epub 2011 Mar 25.

Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS/MNHN, Muséum National d'Histoire Naturelle, 57 Rue Cuvier (CP 54) 75005 Paris, France.

A novel cyclodepsipeptide, iso-isariin B (1), and the known isaridin E (2) were isolated from the entomopathogenic fungus Beauveria felina. Their structures were elucidated using MS/MS fragmentation and extensive 2D-heteronuclear NMR. The X-ray structure of isaridin E was obtained, showing two potent intramolecular H bonds and a type-VI turn with the HyLeu(1)-Pro(2) amide bond in a cis conformation. Iso-isariin B (1) was active against the pest-insect Sitophilus spp. with an LD(50) value of 10 μg/mL. This observation also gives some clues for ecological interpretation of cyclodepsipeptide production by B. felina.
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http://dx.doi.org/10.1021/np100890nDOI Listing
April 2011