Publications by authors named "Christine Beemelmanns"

64 Publications

DAnIEL: A User-Friendly Web Server for Fungal ITS Amplicon Sequencing Data.

Front Microbiol 2021 17;12:720513. Epub 2021 Aug 17.

Systems Biology and Bioinformatics Group, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.

Trillions of microbes representing all kingdoms of life are resident in, and on, humans holding essential roles for the host development and physiology. The last decade over a dozen online tools and servers, accessible public domain, have been developed for the analysis of bacterial sequences; however, the analysis of fungi is still in its infancy. Here, we present a web server dedicated to the comprehensive analysis of the human mycobiome for (i) translating raw sequencing reads to data tables and high-standard figures, (ii) integrating statistical analysis and machine learning with a manually curated relational database and (iii) comparing the user's uploaded datasets with publicly available from the Sequence Read Archive. Using 1,266 publicly available Internal transcribed spacers (ITS) samples, we demonstrated the utility of DAnIEL web server on large scale datasets and show the differences in fungal communities between human skin and soil sites.
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http://dx.doi.org/10.3389/fmicb.2021.720513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416086PMC
August 2021

Comparative Genomic and Metabolic Analysis of sp. RB110 Morphotypes Illuminates Genomic Rearrangements and Formation of a New 46-Membered Antimicrobial Macrolide.

ACS Chem Biol 2021 08 17;16(8):1482-1492. Epub 2021 Jul 17.

Chemical Biology of Microbe-Host Interactions, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Beutenbergstraße 11a, 07745 Jena, Germany.

Morphotype switches frequently occur in Actinobacteria and are often associated with disparate natural product production. Here, we report on differences in the secondary metabolomes of two morphotypes of a species, including the discovery of a novel antimicrobial glycosylated macrolide, which we named termidomycin A. While exhibiting an unusual 46-member polyene backbone, termidomycin A (1) shares structural features with the clinically important antifungal agents amphotericin B and nystatin A1. Genomic analyses revealed a biosynthetic gene cluster encoding for a putative giant type I polyketide synthase (PKS), whose domain structure allowed us to propose the relative configuration of the 46-member macrolide. The architecture of the biosynthetic gene cluster was different in both morphotypes, thus leading to diversification of the product spectrum. Given the high frequency of genomic rearrangements in Streptomycetes, the metabolic analysis of distinct morphotypes as exemplified in this study is a promising approach for the discovery of bioactive natural products and pathways of diversification.
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http://dx.doi.org/10.1021/acschembio.1c00357DOI Listing
August 2021

Genome reduction and relaxed selection is associated with the transition to symbiosis in the basidiomycete genus .

iScience 2021 Jun 1;24(6):102680. Epub 2021 Jun 1.

Section for Ecology and Evolution, Department of Biology, University of Copenhagen, Universitetsparken 15, 2100 Copenhagen Ø, Denmark.

Insights into the genomic consequences of symbiosis for basidiomycete fungi associated with social insects remain sparse. Capitalizing on viability of spores from centuries-old herbarium specimens of free-living, facultative, and specialist termite-associated fungi, we obtained genomes of 10 specimens, including two type species described by Linnaeus >240 years ago. We document that the transition to termite association was accompanied by significant reductions in genome size and gene content, accelerated evolution in protein-coding genes, and reduced functional capacities for oxidative stress responses and lignin degradation. Functional testing confirmed that termite specialists perform worse under oxidative stress, while all lineages retained some capacity to cleave lignin. Mitochondrial genomes of termite associates were significantly larger; possibly driven by smaller population sizes or reduced competition, supported by apparent loss of certain biosynthetic gene clusters. Our findings point to relaxed selection that mirrors genome traits observed among obligate endosymbiotic bacteria of many insects.
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http://dx.doi.org/10.1016/j.isci.2021.102680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220239PMC
June 2021

Two Distinct Bacterial Biofilm Components Trigger Metamorphosis in the Colonial Hydrozoan Hydractinia echinata.

mBio 2021 06 22;12(3):e0040121. Epub 2021 Jun 22.

Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany.

In marine environments, the bacterially induced metamorphosis of larvae is a widespread cross-kingdom communication phenomenon that is critical for the persistence of many marine invertebrates. However, the majority of inducing bacterial signals and underlying cellular mechanisms remain enigmatic. The marine hydroid Hydractinia echinata is a well-known model system for investigating bacterially stimulated larval metamorphosis, as larvae transform into the colonial adult stage within 24 h of signal detection. Although has served as a cell biological model system for decades, the identity and influence of bacterial signals on the morphogenic transition remained largely unexplored. Using a bioassay-guided analysis, we first determined that specific bacterial (lyso)phospholipids, naturally present in bacterial membranes and vesicles, elicit metamorphosis in larvae in a dose-response manner. Lysophospholipids, as single compounds or in combination (50 μM), induced metamorphosis in up to 50% of all larvae within 48 h. Using fluorescence-labeled bacterial phospholipids, we demonstrated that phospholipids are incorporated into the larval membranes, where interactions with internal signaling cascades are proposed to occur. Second, we identified two structurally distinct exopolysaccharides of bacterial biofilms, the new Rha-Man polysaccharide from sp. strain P1-9 and curdlan from Alcaligenes faecalis, to induce metamorphosis in up to 75% of tested larvae. We also found that combinations of (lyso)phospholipids and curdlan induced transformation within 24 h, thereby exceeding the morphogenic activity observed for single compounds and bacterial biofilms. Our results demonstrate that two structurally distinct, bacterium-derived metabolites converge to induce high transformation rates of larvae and thus may help ensure optimal habitat selection. Bacterial biofilms profoundly influence the recruitment and settlement of marine invertebrates, critical steps for diverse marine processes such as the formation of coral reefs, the maintenance of marine fisheries, and the fouling of submerged surfaces. However, the complex composition of biofilms often makes the characterization of individual signals and regulatory mechanisms challenging. Developing tractable model systems to characterize these coevolved interactions is the key to understanding fundamental processes in evolutionary biology. Here, we characterized two types of bacterial signaling molecules, phospholipids and polysaccharides, that induce the morphogenic transition. We then analyzed their abundance and combinatorial activity. This study highlights the general importance of multiple bacterial signal converging activity in development-related cross-kingdom signaling and poses the question of whether complex lipids and polysaccharides are general metamorphic cues for cnidarian larvae.
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http://dx.doi.org/10.1128/mBio.00401-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262903PMC
June 2021

The Termite Fungal Cultivar Combines Diverse Enzymes and Oxidative Reactions for Plant Biomass Conversion.

mBio 2021 06 15;12(3):e0355120. Epub 2021 Jun 15.

Group of Chemical Biology of Microbe-Host Interactions, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Jena, Germany.

Macrotermitine termites have domesticated fungi in the genus as their primary food source using predigested plant biomass. To access the full nutritional value of lignin-enriched plant biomass, the termite-fungus symbiosis requires the depolymerization of this complex phenolic polymer. While most previous work suggests that lignocellulose degradation is accomplished predominantly by the fungal cultivar, our current understanding of the underlying biomolecular mechanisms remains rudimentary. Here, we provide conclusive omics and activity-based evidence that employs not only a broad array of carbohydrate-active enzymes (CAZymes) but also a restricted set of oxidizing enzymes (manganese peroxidase, dye decolorization peroxidase, an unspecific peroxygenase, laccases, and aryl-alcohol oxidases) and Fenton chemistry for biomass degradation. We propose for the first time that induces hydroquinone-mediated Fenton chemistry (Fe + HO + H → Fe + OH + HO) using a herein newly described 2-methoxy-1,4-dihydroxybenzene (2-MHQ, compound 19)-based electron shuttle system to complement the enzymatic degradation pathways. This study provides a comprehensive depiction of how efficient biomass degradation by means of this ancient insect's agricultural symbiosis is accomplished. Fungus-growing termites have optimized the decomposition of recalcitrant plant biomass to access valuable nutrients by engaging in a tripartite symbiosis with complementary contributions from a fungal mutualist and a codiversified gut microbiome. This complex symbiotic interplay makes them one of the most successful and important decomposers for carbon cycling in Old World ecosystems. To date, most research has focused on the enzymatic contributions of microbial partners to carbohydrate decomposition. Here, we provide genomic, transcriptomic, and enzymatic evidence that also employs redox mechanisms, including diverse ligninolytic enzymes and a Fenton chemistry-based hydroquinone-catalyzed lignin degradation mechanism, to break down lignin-rich plant material. Insights into these efficient decomposition mechanisms reveal new sources of efficient ligninolytic agents applicable for energy generation from renewable sources.
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http://dx.doi.org/10.1128/mBio.03551-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262964PMC
June 2021

GNPS-guided discovery of xylacremolide C and D, evaluation of their putative biosynthetic origin and bioactivity studies of xylacremolide A and B.

RSC Adv 2021 May 24;11(31):18748-18756. Epub 2021 May 24.

Chemical Biology of Microbe-Host Interactions, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI) Beutenbergstraße 11a 07745 Jena Germany

Targeted HRMS-GNPS-based metabolomic analysis of sp. X187, a fungal antagonist of the fungus-growing termite symbiosis, resulted in the identification of two lipopeptidic congeners of xylacremolides, named xylacremolide C and D, which are built from d-phenylalanine, l-proline and an acetyl-CoA starter unit elongated by four malonyl-CoA derived ketide units. The putative gene cluster was identified from a draft genome generated by Illumina and PacBio sequencing and RNAseq studies. Biological activities of xylacremolide A and B were evaluated and revealed weak histone deacetylase inhibitory (HDACi) and antifungal activities, as well as moderate protease inhibition activity across a panel of nine human, viral and bacterial proteases.
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http://dx.doi.org/10.1039/d1ra00997dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142242PMC
May 2021

Targeted Isolation of Saalfelduracin B-D from Using LC-MS/MS-Based Molecular Networking.

J Nat Prod 2021 04 8;84(4):1002-1011. Epub 2021 Mar 8.

Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Beutenbergstraße 11a, 07745 Jena, Germany.

High-resolution tandem mass spectrometry (HR-MS)-based metabolomic studies of , isolated from the "Saalfelder Feengrotten" caves in Germany, led to the isolation of three ribosomally synthesized and post-translationally modified type II thiopeptides, saalfelduracin B-D (-) and the known saalfelduracin A (). The structures of all four compounds were determined by comparative two-dimensional NMR analysis and high-resolution tandem mass spectrometry.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01027DOI Listing
April 2021

Comparative Genomics Reveals Prophylactic and Catabolic Capabilities of within the Fungus-Farming Termite Symbiosis.

mSphere 2021 03 3;6(2). Epub 2021 Mar 3.

University of Copenhagen, Department of Biology, Section for Ecology and Evolution, Copenhagen East, Denmark.

, one of the largest bacterial phyla, are ubiquitous in many of Earth's ecosystems and often act as defensive symbionts with animal hosts. Members of the phylum have repeatedly been isolated from basidiomycete-cultivating fungus-farming termites that maintain a monoculture fungus crop on macerated dead plant substrate. The proclivity for antimicrobial and enzyme production of make them likely contributors to plant decomposition and defense in the symbiosis. To test this, we analyzed the prophylactic (biosynthetic gene cluster [BGC]) and metabolic (carbohydrate-active enzyme [CAZy]) potential in 16 (10 existing and six new genomes) termite-associated and compared these to the soil-dwelling close relatives. Using antiSMASH, we identified 435 BGCs, of which 329 (65 unique) were similar to known compound gene clusters, while 106 were putatively novel, suggesting ample prospects for novel compound discovery. BGCs were identified among all major compound categories, including 26 encoding the production of known antimicrobial compounds, which ranged in activity (antibacterial being most prevalent) and modes of action that might suggest broad defensive potential. Peptide pattern recognition analysis revealed 823 (43 unique) CAZymes coding for enzymes that target key plant and fungal cell wall components (predominantly chitin, cellulose, and hemicellulose), confirming a substantial degradative potential of these bacteria. Comparison of termite-associated and soil-dwelling bacteria indicated no significant difference in either BGC or CAZy potential, suggesting that the farming termite hosts may have coopted these soil-dwelling bacteria due to their metabolic potential but that they have not been subject to genome change associated with symbiosis. have repeatedly been isolated in fungus-farming termites, and our genome analyses provide insights into the potential roles they may serve in defense and for plant biomass breakdown. These insights, combined with their relatively higher abundances in fungus combs than in termite gut, suggest that they are more likely to play roles in fungus combs than in termite guts. Up to 25% of the BGCs we identify have no similarity to known clusters, indicating a large potential for novel chemistry to be discovered. Similarities in metabolic potential of soil-dwelling and termite-associated bacteria suggest that they have environmental origins, but their consistent presence with the termite system suggests their importance for the symbiosis.
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http://dx.doi.org/10.1128/mSphere.01233-20DOI Listing
March 2021

Recent highlights of biosynthetic studies on marine natural products.

Org Biomol Chem 2021 01;19(1):123-140

Junior Research Group Chemical Biology of Microbe-Host Interactions, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745 Jena, Germany.

Marine bacteria are excellent yet often underexplored sources of structurally unique bioactive natural products. In this review we cover the diversity of marine bacterial biomolecules and highlight recent studies on structurally novel natural products. We include different compound classes and discuss the latest progress related to their biosynthetic pathway analysis and engineering: examples range from fatty acids over terpenes to PKS, NRPS and hybrid PKS-NRPS biomolecules.
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http://dx.doi.org/10.1039/d0ob01677bDOI Listing
January 2021

Structure elucidation of the redox cofactor mycofactocin reveals oligo-glycosylation by MftF.

Chem Sci 2020 May 23;11(20):5182-5190. Epub 2020 Apr 23.

Junior Research Group Synthetic Microbiology , Leibniz Institute for Natural Product Research and Infection Biology (HKI) , Beutenbergstr. 11a , 07745 Jena , Germany . Email:

Mycofactocin (MFT) is a redox cofactor belonging to the family of ribosomally synthesized and post-translationally modified peptides (RiPPs) and is involved in alcohol metabolism of mycobacteria including . A preliminary biosynthetic model had been established by bioinformatics and studies, while the structure of natural MFT and key biosynthetic steps remained elusive. Here, we report the discovery of glycosylated MFT by C-labeling metabolomics and establish a model of its biosynthesis in . Extensive structure elucidation including NMR revealed that MFT is decorated with up to nine β-1,4-linked glucose residues including 2--methylglucose. Dissection of biosynthetic genes demonstrated that the oligoglycosylation is catalyzed by the glycosyltransferase MftF. Furthermore, we confirm the redox cofactor function of glycosylated MFTs by activity-based metabolic profiling using the carveol dehydrogenase LimC and show that the MFT pool expands during cultivation on ethanol. Our results will guide future studies into the biochemical functions and physiological roles of MFT in bacteria.
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http://dx.doi.org/10.1039/d0sc01172jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491314PMC
May 2020

sp. nov., isolated from the gut of the fungus growing-termite .

Int J Syst Evol Microbiol 2020 Nov;70(11):5806-5811

Leibniz Institute for Natural Product Research and Infection Biology e. V., Hans-Knöll-Institute, Beutenbergstraße 11a, 07745 Jena, Germany.

The taxonomic position of a novel aerobic, Gram-positive actinobacteria, designated strain RB5, was determined using a polyphasic approach. The strain, isolated from the gut of the fungus-farming termite , showed morphological, physiological and chemotaxonomic properties typical of the genus . Based on 16S rRNA gene sequence analysis, the closest phylogenetic neighbour of RB5 was DSM 42102 (98.87 %). DNA-DNA hybridization experiments between strain RB5 and DSM 42102 resulted in a value of 27.4 % (26.8 %). The cell wall of strain RB5 contained ll-diaminopimelic acid as the diagnostic amino acid. Mycolic acids and diagnostic sugars in whole-cell hydrolysates were not detected. The strain produced the following major phospholipids: diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol-mannoside and phosphatidylserine. The menaquinone profile showed hexa- and octahydrogenated menaquinones containing nine isoprene units [MK-9(H) and MK-9(H)]. The strain exhibited a fatty acid profile containing the following major fatty acids: 12-methyltridecanoic acid (iso-C) 12-methyltetradecanoic acid (anteiso-C), 13-methyltetradecanoic acid (iso-C) and 14-methylpentadecanoic acid (iso-C). Here, we propose a novel species of the genus with the type strain RB5 (=VKM Ac-2839=NRRL B65539).
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http://dx.doi.org/10.1099/ijsem.0.004478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723250PMC
November 2020

Polyhalogenation of Isoflavonoids by the Termite-Associated sp. RB99.

J Nat Prod 2020 10 18;83(10):3102-3110. Epub 2020 Sep 18.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.

Based on high-resolution tandem mass spectrometry (HR-MS) and global natural products social molecular networking (GNPS), we found that plant-derived daidzein and genistein derivatives are polyhalogenated by termite-associated species RB99. MS-guided purification from extracts of bacteria grown under optimized conditions led to the isolation of eight polychlorinated isoflavones, including six unreported derivatives, and seven novel polybrominated derivatives, two of which showed antimicrobial activity.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00676DOI Listing
October 2020

sp. nov. and sp. nov., isolated from the gut of the fungus growing-termite .

Int J Syst Evol Microbiol 2020 Oct 26;70(10):5255-5262. Epub 2020 Aug 26.

Chemical Biology of Microbe-Host Interactions, Leibniz Institute for Natural Product Research and Infection Biology e. V., Hans-Knöll-Institute, Beutenbergstraße 11a, 07745 Jena, Germany.

The taxonomic positions of two novel aerobic, Gram-positive actinobacteria, designated strains RB29 and RB68, were determined using a polyphasic approach. Based on 16S rRNA gene sequence analysis, the closest phylogenetic neighbours of RB29 were identified as DSM 102126 (99.2 % similarity) and DSM 43919 (98.7 %), and for strain RB68 was DSM 44148 (98.3 %). Digital DNA-DNA hybridization (dDDH) between RB29 and its closest phylogenetic neighbours, DSM 102126 and DSM 43919, resulted in similarity values of 53.2 % (50.6-55.9 %) and 26.4 % (24.1-28.9 %), respectively. Additionally, the average nucleotide identity (ANI) was 93.2 % (94.0 %) for DSM 102126 and 82.3 % (78.9 %) for DSM 43919. dDDH analysis between strain RB68 and DSM 44148 gave a similarity value of 24.5 % (22.2-27.0 %). Both strains, RB29 and RB68, revealed morphological characteristics and chemotaxonomic features typical for the genus , such as the presence of -diaminopimelic acid in the cell wall, galactose and glucose as major sugar components within whole-cell hydrolysates and the absence of mycolic acids. The major phospholipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannoside. Predominant menaquinones were MK-9(H) and MK-9(H) for RB29 and MK-9(H) and MK-9(H) for RB68. The main fatty acids were identified as 10-methyloctadecanoic acid (10-methyl C), 14-methylpentadecanoic acid (iso-C), hexadecanoic acid (C) and -9-octadecanoic acid (C ω9). Here, we propose two novel species of the genus : sp. nov. with the type strain RB29 (=CCUG 72668=NRRL B-65537) and sp. nov. with the type strain RB68 (=CCUG 72669=NRRL B-65538).
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http://dx.doi.org/10.1099/ijsem.0.004403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660899PMC
October 2020

sp. nov. and sp. nov., isolated from the gut of the fungus-growing termite .

Int J Syst Evol Microbiol 2020 Oct 20;70(10):5226-5234. Epub 2020 Aug 20.

Leibniz Institute for Natural Product Research and Infection Biology e. V., Hans-Knöll-Institute, Beutenbergstraße 11a, 07745 Jena, Germany.

The taxonomic positions of two novel aerobic, Gram-stain-positive Actinobacteria, designated RB20 and RB56, were determined using a polyphasic approach. Both were isolated from the fungus-farming termite . Results of 16S rRNA gene sequence analysis revealed that both strains are members of the genus with the closest phylogenetic neighbours JCM12860 (98.9 %) and DSM44481 (98.5 %) for RB20 and DSM 44801 (98.3 %), DSM 44290 (98.3 %) and JCM 19832 (98.2 %) for RB56. Digital DNA-DNA hybridization (DDH) between RB20 and JCM12860 and DSM 44481 resulted in similarity values of 33.9 and 22.0 %, respectively. DDH between RB56 and DSM44801 and DSM44290 showed similarity values of 20.7 and 22.3 %, respectively. In addition, wet-lab DDH between RB56 and JCM19832 resulted in 10.2 % (14.5 %) similarity. Both strains showed morphological and chemotaxonomic features typical for the genus , such as the presence of -diaminopimelic acid (Apm) within the cell wall, arabinose and galactose as major sugar components within whole cell-wall hydrolysates, the presence of mycolic acids and major phospholipids (diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol), and the predominant menaquinone MK-8 (H, ω-cyclo). The main fatty acids for both strains were hexadecanoic acid (C), 10-methyloctadecanoic acid (10-methyl C) and -9-octadecenoic acid (C ω9). We propose two novel species within the genus : sp. nov. with the type strain RB20 (=VKM Ac-2841=NRRL B65541) and sp. nov. with the type strain RB56 (=VKM Ac-2842=NRRL B65542).
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http://dx.doi.org/10.1099/ijsem.0.004398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660896PMC
October 2020

From Persian Gulf to Indonesia: interrelated phylogeographic distance and chemistry within the genus Peronia (Onchidiidae, Gastropoda, Mollusca).

Sci Rep 2020 08 3;10(1):13048. Epub 2020 Aug 3.

Zoologisches Forschungsmuseum Alexander Koenig, Bonn, Germany.

The knowledge of relationships between taxa is essential to understand and explain the chemical diversity of the respective groups. Here, twelve individuals of the panpulmonate slug Peronia persiae from two localities in Persian Gulf, and one animal of P. verruculata from Bangka Island, Indonesia, were analyzed in a phylogenetic and chemotaxonomic framework. Based on the ABGD test and haplotype networking using COI gene sequences of Peronia specimens, nine well-supported clades were found. Haplotype network analysis highlighted a considerable distance between the specimens of P. persiae and other clades. Metabolomic analysis of both species using tandem mass spectrometry-based GNPS molecular networking revealed a large chemical diversity within Peronia of different clades and localities. While P. persiae from different localities showed a highly similar metabolome, only few identical chemical features were found across the clades. The main common metabolites in both Peronia species were assigned as polypropionate esters of onchitriols and ilikonapyrones, and osmoprotectant amino acid-betaine compounds. On the other hand, the isoflavonoids genistein and daidzein were exclusively detected in P. persiae, while cholesterol and conjugated chenodeoxycholic acids were only found in P. verruculata. Flavonoids, bile acids, and amino acid-betaine compounds were not reported before from Onchidiidae, some are even new for panpulmonates. Our chemical analyses indicate a close chemotaxonomic relation between phylogeographically distant Peronia species.
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http://dx.doi.org/10.1038/s41598-020-69996-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400755PMC
August 2020

Immunomodulatory function of antimicrobial peptide EC-Hepcidin1 modulates the induction of inflammatory gene expression in primary cells of Caspian Trout (Salmo trutta caspius Kessler, 1877).

Fish Shellfish Immunol 2020 Sep 28;104:55-61. Epub 2020 May 28.

Leibniz Institute for Natural Product Research and Infection Biology e.V. Hans-Knöll-Institute (HKI), Jena, Germany. Electronic address:

Hepcidins, a group of antimicrobial peptides (AMPs), play a key role in the innate immune system of fishes and act against different pathogens. In this study, antimicrobial and immune-inflammatory activity of a synthetic EC-hepcidin1, previously identified from orange-spotted grouper, were evaluated. EC-hepcidin1 showed weak activity against the zoonotic fish pathogen Streptococcus iniae (MIC 100 μg mL and MBC 150 μg mL). To study the effect of AMPs in general, and EC-hepcidin1 in particular, a primary cell culture (SC) from the fin tissue of the Caspian Trout (Salmo trutta caspius) was established. The neutral Red method on SC cells revealed that EC-hepcidin1 has no or very low cytotoxic properties. Treatment of cells with either EC-hepcidin1 (150 μg mL) or fish pathogen Streptococcus iniae (MOI = 10) and a mixture of both resulted in the up-regulation of gene expression of MHC-UBA, IL-6, and TNFα indicating the modulatory function on inflammatory processes. These findings indicate that EC-hepcidin1 might act as a candidate for modulation of the innate immune system in S. iniae-based infection.
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http://dx.doi.org/10.1016/j.fsi.2020.05.067DOI Listing
September 2020

Targeted Discovery of Tetrapeptides and Cyclic Polyketide-Peptide Hybrids from a Fungal Antagonist of Farming Termites.

Chembiochem 2020 10 2;21(20):2991-2996. Epub 2020 Jul 2.

Chemical Biology of Microbe - Host Interactions, Institution Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Beutenbergstrasse 11a, 07745, Jena, Germany.

Herein, we report the targeted isolation and characterization of four linear nonribosomally synthesized tetrapeptides (pseudoxylaramide A-D) and two cyclic nonribosomal peptide synthetase-polyketide synthase-derived natural products (xylacremolide A and B) from the termite-associated stowaway fungus Pseudoxylaria sp. X187. The fungal strain was prioritized for further metabolic analysis based on its taxonomical position and morphological and bioassay data. Metabolic data were dereplicated based on high-resolution tandem mass spectrometry data and global molecular networking analysis. The structure of all six new natural products was elucidated based on a combination of 1D and 2D NMR analysis, Marfey's analysis and X-ray crystallography.
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http://dx.doi.org/10.1002/cbic.202000331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689812PMC
October 2020

Modular Solid-Phase Synthesis of Antiprotozoal Barnesin Derivatives.

Org Lett 2020 05 26;22(10):3744-3748. Epub 2020 Mar 26.

Leibniz Institute for Natural-Product Research and Infection Biology - Hans Knöll Institute (HKI), Beutenbergstraβe 11a, 07745 Jena, Germany.

Here, we applied and optimized a solid support (SP)-based Horner-Wadsworth-Emmons reagent to prepare SP-bound vinylogous amino acids. Subsequent SP-based peptide synthesis, global deprotection, and chemical modifications yielded 14 lipodipeptides carrying vinylogous amino acids, including the natural product barnesin A (). Biological evaluation revealed that several synthesized derivatives show micromolar to nanomolar inhibitory activity against papain-like cysteine proteases, human cathepsin L, and rhodesain.
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http://dx.doi.org/10.1021/acs.orglett.0c00723DOI Listing
May 2020

Xyloneside A: A New Glycosylated Incisterol Derivative from Xylaria sp. FB.

Chembiochem 2020 08 5;21(16):2253-2258. Epub 2020 May 5.

School of Pharmacy, Sungkyunkwan University, Suwon, 16419 (Republic of, Korea.

Xylaria species are prolific natural product producers. Here, we report the characterization of a new glycosylated incisterol derivative, called xyloneside A (1) and two known lignans (2 and 3) from the ascomycetous Xylaria sp. FB. The structure of xyloneside A (1) was determined by 1D and 2D NMR spectroscopy, high-resolution electrospray ionization mass spectrometry and electronic circular dichroism measurements. Xyloneside A is composed of a 1,2,3,4,5,10,19-heptanorergosterane skeleton and a β-D-mannopyranose moiety. This is the first report of an incisterol derivative from an Ascomycete. The biological effects of the isolated metabolites on cytotoxicity, autophagy, cell-migration, and angiogenesis were evaluated.
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http://dx.doi.org/10.1002/cbic.202000065DOI Listing
August 2020

Gene Cluster Activation in a Bacterial Symbiont Leads to Halogenated Angucyclic Maduralactomycins and Spirocyclic Actinospirols.

Org Lett 2020 04 20;22(7):2634-2638. Epub 2020 Mar 20.

Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (HKI), Beutenbergstraße 11a, 07745 Jena, Germany.

Growth from spores activated a biosynthetic gene cluster in sp. RB29, resulting in the identification of two novel groups of halogenated polyketide natural products, named maduralactomycins and actinospirols. The unique tetracyclic and spirocyclic structures were assigned based on a combination of NMR analysis, chemoinformatic calculations, X-ray crystallography, and C labeling studies. On the basis of HRMS data, genome mining, and gene expression studies, we propose an underlying noncanonical angucycline biosynthesis and extensive post-polyketide synthase (PKS) oxidative modifications.
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http://dx.doi.org/10.1021/acs.orglett.0c00601DOI Listing
April 2020

Absolute Configuration and Corrected NMR Assignment of 17-Hydroxycyclooctatin, a Fused 5-8-5 Tricyclic Diterpene.

J Nat Prod 2020 02 28;83(2):354-361. Epub 2020 Jan 28.

School of Pharmacy , Sungkyunkwan University , Suwon 16419 , Republic of Korea.

The absolute configuration and corrected NMR assignment of 17-hydroxycyclooctatin isolated from sp. M56 recovered from a nest of South African termites are reported. 17-Hydroxycyclooctatin is a unique tricyclic diterpene (C) consisting of a fused 5-8-5 ring system, and in this study, its structure was unambiguously determined by a combination of HR-ESIMS and 1D and 2D NMR spectroscopic experiments to produce corrected NMR assignments. The absolute configuration of 17-hydroxycyclooctatin is reported for the first time in the current study using chemical reactions and quantum chemical ECD calculations. The corrected NMR assignments were verified using a gauge-including atomic orbital NMR chemical shifts calculation, followed by DP4 probability. To understand the pharmacological properties of 17-hydroxycyclooctatin, a network pharmacological approach and molecular docking analyses were used, which also predicted its effects on human breast cancer cell lines. Cytotoxicity and antiestrogenic activity of 17-hydroxycyclooctatin were determined, and it was found this compound may be an ERα antagonist.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00837DOI Listing
February 2020

Hybrid Polyketides from a -Associated SW67 and Their Putative Biosynthetic Origin.

Mar Drugs 2019 Oct 24;17(11). Epub 2019 Oct 24.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Five hybrid polyketides (, , and -) containing tetramic acid core including a new hybrid polyketide, cladosin L (), were isolated from the marine fungus SW67, which was isolated from the marine hydroid polyp of . The hybrid polyketides were isolated as a pair of interconverting geometric isomers. The structure of was determined based on 1D and 2D NMR spectroscopic and HR-ESIMS analyses. Its absolute configuration was established by quantum chemical electronic circular dichroism (ECD) calculations and modified Mosher's method. Tetramic acid-containing compounds are reported to be derived from a hybrid PKS-NRPS, which was also proved by analyzing our C-labeling data. We investigated whether compounds - could prevent cell damage induced by cisplatin, a platinum-based anticancer drug, in LLC-PK1 cells. Co-treatment with and ameliorated the damage of LLC-PK1 cells induced by 25 μM of cisplatin. In particular, the effect of compound at 100 μM (cell viability, 90.68 ± 0.81%) was similar to the recovered cell viability of 88.23 ± 0.25% with 500 μM -acetylcysteine (NAC), a positive control.
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http://dx.doi.org/10.3390/md17110606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891565PMC
October 2019

Metabolic Pathway Rerouting in Evolved Long-Overlooked Derivatives of Coenzyme F.

ACS Chem Biol 2019 09 11;14(9):2088-2094. Epub 2019 Sep 11.

Junior Research Group Synthetic Microbiology , Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute , Beutenbergstr. 11a , 07745 Jena , Germany.

Coenzyme F is a specialized redox cofactor with a negative redox potential. It supports biochemical processes like methanogenesis, degradation of xenobiotics, and the biosynthesis of antibiotics. Although well-studied in methanogenic archaea and actinobacteria, not much is known about F in Gram-negative bacteria. Genome sequencing revealed F biosynthetic genes in the Gram-negative, endofungal bacterium , a symbiont of phytopathogenic fungi. Fluorescence microscopy, high-resolution LC-MS, and structure elucidation by NMR demonstrated that the encoded pathway is active and yields unexpected derivatives of F (3PG-F). Further analyses of a biogas-producing microbial community showed that these derivatives are more widespread in nature. Genetic and biochemical studies of their biosynthesis established that a specificity switch in the guanylyltransferase CofC reprogrammed the pathway to start from 3-phospho-d-glycerate, suggesting a rerouting event during the evolution of F biosynthesis. Furthermore, the cofactor activity of 3PG-F was validated, thus opening up perspectives for its use in biocatalysis. The 3PG-F biosynthetic gene cluster is fully functional in , enabling convenient production of the cofactor by fermentation.
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http://dx.doi.org/10.1021/acschembio.9b00605DOI Listing
September 2019

Efomycins K and L From a Termite-Associated sp. M56 and Their Putative Biosynthetic Origin.

Front Microbiol 2019 6;10:1739. Epub 2019 Aug 6.

School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.

Two new elaiophylin derivatives, efomycins K () and L (), and five known elaiophylin derivatives () were isolated from the termite-associated sp. M56. The structures were determined by 1D and 2D NMR and HR-ESIMS analyses and comparative CD spectroscopy. The putative gene cluster responsible for the production of the elaiophylin and efomycin derivatives was identified based on significant homology to related clusters. Phylogenetic analysis of gene cluster domains was used to provide a biosynthetic rational for these new derivatives and to demonstrate how a single biosynthetic pathway can produce diverse structures.
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http://dx.doi.org/10.3389/fmicb.2019.01739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691879PMC
August 2019

Disease-free monoculture farming by fungus-growing termites.

Sci Rep 2019 06 19;9(1):8819. Epub 2019 Jun 19.

Section for Ecology and Evolution, Department of Biology, University of Copenhagen, Universitetsparken 15, Building 3, 2100, Copenhagen East, Denmark.

Fungus-growing termites engage in an obligate mutualistic relationship with Termitomyces fungi, which they maintain in monocultures on specialised fungus comb structures, without apparent problems with infectious diseases. While other fungi have been reported in the symbiosis, detailed comb fungal community analyses have been lacking. Here we use culture-dependent and -independent methods to characterise fungus comb mycobiotas from three fungus-growing termite species (two genera). Internal Transcribed Spacer (ITS) gene analyses using 454 pyrosequencing and Illumina MiSeq showed that non-Termitomyces fungi were essentially absent in fungus combs, and that Termitomyces fungal crops are maintained in monocultures as heterokaryons with two or three abundant ITS variants in a single fungal strain. To explore whether the essential absence of other fungi within fungus combs is potentially due to the production of antifungal metabolites by Termitomyces or comb bacteria, we performed in vitro assays and found that both Termitomyces and chemical extracts of fungus comb material can inhibit potential fungal antagonists. Chemical analyses of fungus comb material point to a highly complex metabolome, including compounds with the potential to play roles in mediating these contaminant-free farming conditions in the termite symbiosis.
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http://dx.doi.org/10.1038/s41598-019-45364-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584615PMC
June 2019

Stereoselective synthesis of unnatural (2S,3S)-6-hydroxy-4-sphingenine-containing sphingolipids.

Org Biomol Chem 2019 08 28;17(29):6964-6969. Epub 2019 May 28.

Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Beutenbergstraße 11a, D-07745 Jena, Germany.

6-Hydroxy-(4E)-sphingenine-containing sphingolipids are found in mammalian and bacterial membranes and have multiple intra- and intercellular functions. Most sphingolipids contain a (2S,3R)-2-amino-1,3-diol core structure, but only limited examples of unnatural (2S,3S)-2-amino-1,3-diol derivates have so far been reported. Using an underexplored hydrozirconation-transmetalation reaction and an unusual three-step-one-pot deprotection sequence, we were able to synthesize several unnatural (2S,3S)-6-hydroxy-(4E)-sphingenine-containing sphingolipids in only three (protected) or four (deprotected) consecutive steps, respectively, including a fluoresence-labeled derivative suitable for future biological studies.
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http://dx.doi.org/10.1039/c9ob00990fDOI Listing
August 2019

Stereoselective Cascade Cyclizations with Samarium Diiodide to Tetracyclic Indolines: Precursors of Fluorostrychnines and Brucine.

Chemistry 2019 Jul 5;25(37):8780-8789. Epub 2019 Jun 5.

Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195, Berlin, Germany.

A series of γ-indolylketones with fluorine, cyano or alkoxy substituents at the benzene moiety was prepared and subjected to samarium diiodide-promoted cyclization reactions. The desired dearomatizing ketyl cascade reaction forming two new rings proceeded in all cases with high diastereoselectivity, but with differing product distribution. In most cases, the desired annulated tetracyclic compounds were obtained in moderate to good yields, but as second product tetracyclic spirolactones were isolated in up to 29 % yield. The reaction rate was influenced by the substituents at the benzene moiety of the substrate as expected, with electron-accepting groups accelerating and electron-donating groups decelerating the cyclization process. In case of a difluoro-substituted γ-indolylketone a partial defluorination was observed. The intermediate samarium enolate of the tetracyclic products could be trapped by adding reactive alkylating agents as electrophiles delivering products with quarternary carbons. In the case of a dimethoxy-substituted tetracyclic cyclization product a subsequent reductive amination stereoselectively provided a pentacyclic compound that was subsequently N-protected and subjected to a regioselective elimination. The obtained functionalized pentacyclic product should be convertible into the alkaloid brucine by four well-established steps. Overall, the presented report shows that functionalized tetracyclic compounds with different substituents are rapidly available with the samarium diiodide cascade cyclization as crucial step. Hence, analogues of the landmark alkaloid strychnine, for example, with specific fluorine substitutions, should be easily accessible.
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http://dx.doi.org/10.1002/chem.201900087DOI Listing
July 2019

Fridamycin A, a Microbial Natural Product, Stimulates Glucose Uptake without Inducing Adipogenesis.

Nutrients 2019 Apr 1;11(4). Epub 2019 Apr 1.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Type 2 diabetes is a complex, heterogeneous, and polygenic disease. Currently, available drugs for treating type 2 diabetes predominantly include sulfonylureas, α-glucosidase inhibitors, and biguanides. However, long-term treatment with these therapeutic drugs is often accompanied by undesirable side effects, which have driven interest in the development of more effective and safer antidiabetic agents. To address the urgent need for new chemical solutions, we focused on the analysis of structurally novel and/or biologically new metabolites produced by insect-associated microbes as they have recently been recognized as a rich source of natural products. Comparative LC/MS-based analysis of Actinomadura sp. RB99, isolated from a fungus-growing termite, led to the identification of the type II polyketide synthase-derived fridamycin A. The structure of fridamycin A was confirmed by ¹H NMR data and LC/MS analysis. The natural microbial product, fridamycin A, was examined for its antidiabetic properties in 3T3-L1 adipocytes, which demonstrated that fridamycin A induced glucose uptake in 3T3-L1 cells by activating the AMP-activated protein kinase (AMPK) signaling pathway but did not affect adipocyte differentiation, suggesting that the glucose uptake took place through activation of the AMPK signaling pathway without inducing adipogenesis. Our results suggest that fridamycin A has potential to induce fewer side effects such as weight gain compared to rosiglitazone, a commonly used antidiabetic drug, and that fridamycin A could be a novel potential therapeutic candidate for the management of type 2 diabetes.
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http://dx.doi.org/10.3390/nu11040765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520714PMC
April 2019

Reviewing the taxonomy of Podaxis: Opportunities for understanding extreme fungal lifestyles.

Fungal Biol 2019 03 11;123(3):183-187. Epub 2019 Jan 11.

Section for Ecology and Evolution, Department of Biology, University of Copenhagen, Copenhagen, Denmark.

There are few environments more hostile and species-poor than deserts and the mounds of Nasutitermitinae termites. However, despite the very different adaptations required to survive in such extreme and different environments, the fungal genus Podaxis is capable of surviving in both: where few other fungi are reported to grow. Despite their prominence in the landscape and their frequent documentation by early explorers, there has been relatively little research into the genus. Originally described by Linnaeus in 1771, in the early 20th Century, the then ∼25 species of Podaxis were almost entirely reduced into one species: Podaxis pistillaris. Since this reduction, several new species of Podaxis have been described but without consideration of older descriptions. This has resulted in 44 recognised species names in Index Fungorum but the vast majority of studies and fungarium specimens still refer to P. pistillaris. Studies of Podaxis' extremely different lifestyles is hampered by its effective reduction to a single-species genus. Here we examine the history of the taxonomy of Podaxis before focusing on its extreme lifestyles. From this, we consider how the muddled taxonomy of Podaxis may be resolved; opening up further avenues for future research into this enigmatic fungal genus.
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http://dx.doi.org/10.1016/j.funbio.2019.01.001DOI Listing
March 2019
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