Publications by authors named "Hans-Martin Dahse"

109 Publications

New Guaianolide Sesquiterpene Lactones and Other Constituents from Pyrethrum pulchrum.

Planta Med 2021 Aug 5. Epub 2021 Aug 5.

Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia.

is a rare Mongolian plant species that has been traditionally used as an ingredient in various remedies. Bioactivity-guided fractionation performed on the methanol extract of its aerial parts led to the isolation of 2 previously undescribed guaianolide-type sesquiterpene lactones, namely 1,10-epoxy-8-hydroxyguaia-3,11(13)-dien-6,12-olide (1: ) and 1,8,10-trihydroxyguaia-3,11(13)-dien-6,12-olide (2: ), along with the isolation or chromatographic identification of 11 compounds, arglabin (3: ), 3-hydroxycostunolide (4: ), isocostic acid (5: ), ()-9-(2-thienyl)-6-nonen-8-yn-3-ol (6: ), ()-9-(2-thienyl)-6-nonen-8-yn-3-ol (7: ), , , , -tetra-p-coumaroyl spermine (8: ), chlorogenic acid (9: ), 3,5-di--caffeoylquinic acid (10: ), 3,5-di--caffeoylquinic acid methyl ester (11: ), 3,4-di--caffeoylquinic acid (12: ), and tryptophan (13: ). Their structures were assigned based on spectroscopic and spectrometric data. The antimicrobial, antiproliferative and cytotoxic activities of selected compounds were evaluated. The new compounds showed weak to moderate antimicrobial activity. Arglabin (3: ), the major sesquiterpene lactone found in the methanol extract of , exhibited the highest activity against human cancer lines, while compound 1: also possesses significant antiproliferative activity against leukemia cells.
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http://dx.doi.org/10.1055/a-1554-2866DOI Listing
August 2021

Total Synthesis and Bioactivity Mapping of Geodiamolide H.

Chemistry 2021 Aug 25;27(45):11633-11642. Epub 2021 Jun 25.

Institut für Organische Chemie und Makromolekulare Chemie, Friedrich-Schiller-Universität (FSU), Humboldtstr. 10, 07743, Jena, Germany.

The first total synthesis of the actin-stabilizing marine natural product geodiamolide H was achieved. Solid-phase based peptide assembly paired with scalable stereoselective syntheses of polyketide building blocks and an optimized esterification set the stage for investigating the key ring-closing metathesis. Geodiamolide H and synthetic analogues were characterized for their toxicity and for antiproliferative effects in cellulo, by characterising actin polymerization induction in vitro, and by docking on the F-actin target and property computation in silico, for a better understanding of structure-activity relationships (SAR). A non-natural analogue of geodiamolide H was discovered to be most potent in the series, suggesting significant potential for tool compound design.
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http://dx.doi.org/10.1002/chem.202100989DOI Listing
August 2021

Potential Cancer- and Alzheimer's Disease-Targeting Phosphodiesterase Inhibitors from : Insights from and Consensus Virtual Screening.

ACS Omega 2021 Mar 16;6(12):8403-8417. Epub 2021 Mar 16.

Laboratory of Organic Reactivity, Discovery & Synthesis (LORDS), Research Center for Natural & Applied Sciences, University of Santo Tomas, España Blvd., 1015 Manila, Philippines.

Inhibition of the major cyclic adenosine monophosphate-metabolizing enzyme PDE4 has shown potential for the discovery of drugs for cancer, inflammation, and neurodegenerative disorders such as Alzheimer's disease. As a springboard to explore new anti-cancer and anti-Alzheimer's chemical prototypes from rare Annonaceae species, the present study evaluated anti-PDE4B along with antiproliferative and anti-cholinesterase activities of the extracts of the Philippine endemic species using assays and framed the resulting biological significance through computational binding and reactivity-based experiments. Thus, the PDE4 B2B-inhibiting dichloromethane sub-extract (UaD) of elicited antiproliferative activity against chronic myelogenous leukemia (K-562) and cytostatic effects against human cervical cancer (HeLa). The extract also profoundly inhibited acetylcholinesterase (AChE), an enzyme involved in the progression of neurodegenerative diseases. Chemical profiling analysis of the bioactive extract identified 18 putative secondary metabolites. Molecular docking and molecular dynamics simulations showed strong free energy binding mechanisms and dynamic stability at 50-ns simulations in the catalytic domains of PDE4 B2B, ubiquitin-specific peptidase 14, and Kelch-like ECH-associated protein 1 (KEAP-1 Kelch domain) for the benzylated dihydroflavone dichamanetin (), and of an AChE and KEAP-1 BTB domain for 3-(3,4-dihydroxybenzyl)-3',4',6-trihydroxy-2,4-dimethoxychalcone () and grandifloracin (), respectively. Density functional theory calculations to demonstrate Michael addition reaction of the most electrophilic metabolite and kinetically stable grandifloracin () with Cys151 of the KEAP-1 BTB domain illustrated favorable formation of a β-addition adduct. The top-ranked compounds also conferred favorable pharmacokinetic properties.
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http://dx.doi.org/10.1021/acsomega.1c00137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015132PMC
March 2021

Antibacterial and COX-2 Inhibitory Tetrahydrobisbenzylisoquinoline Alkaloids from the Philippine Medicinal Plant .

Plants (Basel) 2021 Mar 1;10(3). Epub 2021 Mar 1.

Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, España Blvd., Manila 1015, Philippines.

(Roxb. ex G.Don) J.Sinclair (previously known as (Presl) Merr) is a Philippine medicinal plant occurring as evergreen shrub in the lowland forests of Luzon islands. It is used traditionally by Filipinos to treat bacterial conjunctivitis, ulcer and wound infections. Based on previous investigations where cyclooxygenase-2 (COX-2) functions as immune-linked factor in infectious sensitivities to bacterial pathogens by triggering pro-inflammatory immune-associated reactions, we investigated the antimicrobial and COX inhibitory activities of the extracts and tetrahydrobisbenzylisoquinoline alkaloids of in vitro and in silico to validate its ethnomedicinal uses. Thus, the dichloromethane-methanol (DCM-MeOH) crude extract and alkaloid extracts exhibiting antibacterial activities against drug-resistant bacterial strains such as methicillin-resistance (MRSA), vancomycin-resistant (VRE), + CRE and + MBL afforded (+)-tetrandrine () and (+)-limacusine () as the major biologically active tetrahydrobisbenzylisoquinoline alkaloidal constituents after purification. Both tetrahydrobisbenzylisoquinoline alkaloids and showed broad spectrum antibacterial activity with strongest inhibition against the Gram-negative bacteria MβL- + CRE. Interestingly, the alkaloid limacusine () showed selective inhibition against ovine COX-2 in vitro. These results were ascertained by molecular docking and molecular dynamics simulation experiments where alkaloid showed strong affinity in the catalytic sites of Gram-negative bacterial enzymes elastase and KPC-2 carbapenemase (enzymes involved in infectivity mechanisms), and of ovine COX-2. Overall, our study provides credence on the ethnomedicinal use of the Philippine medicinal plant as traditional plant-based adjuvant to treat bacterial conjunctivitis and other related infections. The antibacterial activities and selective COX-2 inhibition observed for limacusine () point to its role as the biologically active constituent of A limited number of drugs with COX-2 inhibitory properties like celecoxib also confer antibacterial activity. Thus, tetrahydrobisbenzyl alkaloids, especially , are promising pharmaceutical inspirations for developing treatments of bacterial/inflammation-related infections.
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http://dx.doi.org/10.3390/plants10030462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999448PMC
March 2021

The impact of episporic modification of on virulence and interaction with phagocytes.

Comput Struct Biotechnol J 2021 20;19:880-896. Epub 2021 Jan 20.

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

Fungal infections caused by the ancient lineage Mucorales are emerging and increasingly reported in humans. Comprehensive surveys on promising attributes from a multitude of possible virulence factors are limited and so far, focused on and . This study addresses a systematic approach to monitor phagocytosis after physical and enzymatic modification of the outer spore wall of , one of the major causative agents of mucormycosis. Episporic modifications were performed and their consequences on phagocytosis, intracellular survival and virulence by murine alveolar macrophages and in an invertebrate infection model were elucidated. While depletion of lipids did not affect the phagocytosis of both strains, delipidation led to attenuation of LCA strain but appears to be dispensable for infection with LCV strain in the settings used in this study. Combined glucano-proteolytic treatment was necessary to achieve a significant decrease of virulence of the LCV strain in during maintenance of the full potential for spore germination as shown by a novel automated germination assay. Proteolytic and glucanolytic treatments largely increased phagocytosis compared to alive resting and swollen spores. Whilst resting spores barely (1-2%) fuse to lysosomes after invagination in to phagosomes, spore trypsinization led to a 10-fold increase of phagolysosomal fusion as measured by intracellular acidification. This is the first report of a polyphasic measurement of the consequences of episporic modification of a mucormycotic pathogen in spore germination, spore surface ultrastructure, phagocytosis, stimulation of Toll-like receptors (TLRs), phagolysosomal fusion and intracellular acidification, apoptosis, generation of reactive oxygen species (ROS) and virulence.
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http://dx.doi.org/10.1016/j.csbj.2021.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851798PMC
January 2021

Bioactive flavonoids from plant extract of and its acute toxicity.

Nat Prod Res 2020 Aug 17:1-4. Epub 2020 Aug 17.

Department of Chemistry, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia.

Ledeb. has been a phytochemically unexplored Mongolian medicinal folklore plant. In this study, its total flavonoid content was determined and fourteen flavonoids () were isolated from the aerial parts of . Their structures were elucidated on the basis of spectroscopic data. The compounds -, methoxyflavones, were tested for antiproliferative and cytotoxic activity against A549, HeLa, K-562, THP-1 and HUVEC cell lines. This is the first report on the effects of 5,7,4'-trihydroxy-3,6,3'-trimethoxyflavone () against all tested cell lines and it exhibited potent activity against chronic myeloid leukemia K-562 and acute monocytic leukemia THP-1 cells, each with GI value at 2.0 μg/mL. The 5,4'-dihydroxy-3,6,7,3'-tetramethoxyflavone () showed the most potent activity against THP-1 (GI = 1.1 μg/mL) and the highest cytotoxicity (5.6 μg/mL). In addition, acute toxicity of plant ethanol extract was evaluated and the lethal dose (LD) was estimated at 1048 mg/kg.
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http://dx.doi.org/10.1080/14786419.2020.1806271DOI Listing
August 2020

Functional surface proteomic profiling reveals the host heat-shock protein A8 as a mediator of Lichtheimia corymbifera recognition by murine alveolar macrophages.

Environ Microbiol 2020 09 21;22(9):3722-3740. Epub 2020 Jul 21.

Jena Microbial Resource Collection, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (HKI), Jena, Germany.

Mucormycosis is an emergent, fatal fungal infection of humans and warm-blooded animals caused by species of the order Mucorales. Immune cells of the innate immune system serve as the first line of defence against inhaled spores. Alveolar macrophages were challenged with the mucoralean fungus Lichtheimia corymbifera and subjected to biotinylation and streptavidin enrichment procedures followed by LC-MS/MS analyses. A total of 28 host proteins enriched for binding to macrophage-L. corymbifera interaction. Among those, the HSP70-family protein Hspa8 was found to be predominantly responsive to living and heat-killed spores of a virulent and an attenuated strain of L. corymbifera. Confocal scanning laser microscopy of infected macrophages revealed colocalization of Hspa8 with phagocytosed spores of L. corymbifera. The amount of detectable Hspa8 was dependent on the multiplicity of infection. Incubation of alveolar macrophages with an anti-Hspa8 antibody prior to infection reduced their capability to phagocytose spores of L. corymbifera. In contrast, anti-Hspa8 antibodies did not abrogate the phagocytosis of Aspergillus fumigatus conidia by macrophages. These results suggest an important contribution of the heat-shock family protein Hspa8 in the recognition of spores of the mucoralean fungus L. corymbifera by host alveolar macrophages and define a potential immunomodulatory therapeutic target.
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http://dx.doi.org/10.1111/1462-2920.15140DOI Listing
September 2020

Quantitative Impact of Cell Membrane Fluorescence Labeling on Phagocytosis Measurements in Confrontation Assays.

Front Microbiol 2020 5;11:1193. Epub 2020 Jun 5.

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

Phagocytosis is series of steps where the pathogens and the immune cells interact during an invasion. This starts with the adhesion process between the host and pathogen cells, and is followed by the engulfment of the pathogens. Many analytical methods that are applied to characterize phagocytosis based on imaging the host-pathogen confrontation assays rely on the fluorescence labeling of cells. However, the potential effect of the membrane labeling on the quantitative results of the confrontation assays has not been studied in detail. In this study, we determine whether the fluorescence labeling processes themselves influence the results of the phagocytosis measurements. Here, alveolar macrophages, which form one of the most important compartments of the innate immune system, were used as an example of host cells, whereas and that cause aspergillosis and mucormycosis, respectively, were studied as examples for pathogens. At first, our study investigated the importance of the sequence of steps of the fixation process when preparing the confrontation assay sample for microscopy studies. Here we showed that applying the fixation agent before the counter-staining causes miscalculations during the determination of the phagocytic measures. Furthermore, we also found that staining the macrophages with various concentrations of DID, as a typical membrane label, in most cases altered the capability of macrophages to phagocytose FITC-stained and spores in comparison with unlabeled macrophages. This effect of the DID staining showed a differential character dependent upon the labeling status and the specific type of pathogen. Moreover, labeling the spores of and with FITC increased the phagocytic measures during confrontation with unlabeled macrophages when compared to label-free spores. Overall, our study confirms that the staining process itself may significantly manipulate the quantitative outcome of the confrontation assay. As a result of our study, we also developed a user-friendly image analysis tool that analyses confrontation assays both with and without fluorescence labeling of the host cells and of the pathogens. Our image analysis algorithm saves experimental work effort and time, provides more precise results when calculating the phagocytic measures, and delivers a convenient analysis tool for the biologists to monitor host-pathogen interactions as they happen without the artifacts that fluorescence labeling imposes on biological interactions.
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http://dx.doi.org/10.3389/fmicb.2020.01193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289966PMC
June 2020

Antitubercular and cytotoxic polyoxygenated cyclohexane derivatives from .

Nat Prod Res 2020 Mar 23:1-4. Epub 2020 Mar 23.

Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.

Chromatographic purification of the DCM sub-extract of led to the isolation and characterization of a new polyoxygenated cyclohexane derivative, grandifloranol (), together with five known compounds. Among the compounds isolated, zeylenone () showed moderate antitubercular activity against HRv with MIC value of 51.2 μM and antiproliferative or cytotoxic activity against human myeloid leukaemia (K-562) and HeLa cells with IC values of 2.3 and 18.3 μM, respectively.
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http://dx.doi.org/10.1080/14786419.2020.1741579DOI Listing
March 2020

Mining Symbionts of a Spider-Transmitted Fungus Illuminates Uncharted Biosynthetic Pathways to Cytotoxic Benzolactones.

Angew Chem Int Ed Engl 2020 05 18;59(20):7766-7771. Epub 2020 Mar 18.

Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Chemistry and Infection Biology (HKI), Beutenbergstr. 11a, 07745, Jena, Germany.

A spider-transmitted fungus (Rhizopus microsporus) that was isolated from necrotic human tissue was found to harbor endofungal bacteria (Burkholderia sp.). Metabolic profiling of the symbionts revealed a complex of cytotoxic agents (necroximes). Their structures were characterized as oxime-substituted benzolactone enamides with a peptidic side chain. The potently cytotoxic necroximes are also formed in symbiosis with the fungal host and could have contributed to the necrosis. Genome sequencing and computational analyses revealed a novel modular PKS/NRPS assembly line equipped with several non-canonical domains. Based on gene-deletion mutants, we propose a biosynthetic model for bacterial benzolactones. We identified specific traits that serve as genetic handles to find related salicylate macrolide pathways (lobatamide, oximidine, apicularen) in various other bacterial genera. Knowledge of the biosynthetic pathway enables biosynthetic engineering and genome-mining approaches.
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http://dx.doi.org/10.1002/anie.201916007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318616PMC
May 2020

Cyclopropanol Warhead in Malleicyprol Confers Virulence of Human- and Animal-Pathogenic Burkholderia Species.

Angew Chem Int Ed Engl 2019 10 27;58(40):14129-14133. Epub 2019 Aug 27.

Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745, Jena, Germany.

Burkholderia species such as B. mallei and B. pseudomallei are bacterial pathogens causing fatal infections in humans and animals (glanders and melioidosis), yet knowledge on their virulence factors is limited. While pathogenic effects have been linked to a highly conserved gene locus (bur/mal) in the B. mallei group, the metabolite associated to the encoded polyketide synthase, burkholderic acid (syn. malleilactone), could not explain the observed phenotypes. By metabolic profiling and molecular network analyses of the model organism B. thailandensis, the primary products of the cryptic pathway were identified as unusual cyclopropanol-substituted polyketides. First, sulfomalleicyprols were identified as inactive precursors of burkholderic acid. Furthermore, a highly reactive upstream metabolite, malleicyprol, was discovered and obtained in two stabilized forms. Cell-based assays and a nematode infection model showed that the rare natural product confers cytotoxicity and virulence.
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http://dx.doi.org/10.1002/anie.201907324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790655PMC
October 2019

The geographical region of origin determines the phagocytic vulnerability of Lichtheimia strains.

Environ Microbiol 2019 12 5;21(12):4563-4581. Epub 2019 Aug 5.

Institute of Microbiology, Faculty of Biological Sciences, Friedrich Schiller University Jena, Jena, Germany.

Mucormycoses are life-threatening infections that affect patients suffering from immune deficiencies. We performed phagocytosis assays confronting various strains of Lichtheimia species with alveolar macrophages, which form the first line of defence of the innate immune system. To investigate 17 strains from four different continents in a comparative fashion, transmitted light and confocal fluorescence microscopy was applied in combination with automated image analysis. This interdisciplinary approach enabled the objective and quantitative processing of the big volume of image data. Applying machine-learning supported methods, a spontaneous clustering of the strains was revealed in the space of phagocytic measures. This clustering was not driven by measures of fungal morphology but rather by the geographical origin of the fungal strains. Our study illustrates the crucial contribution of machine-learning supported automated image analysis to the qualitative discovery and quantitative comparison of major factors affecting host-pathogen interactions. We found that the phagocytic vulnerability of Lichtheimia species depends on their geographical origin, where strains within each geographic region behaved similarly, but strongly differed amongst the regions. Based on this clustering, we were able to also classify clinical isolates with regard to their potential geographical origin.
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http://dx.doi.org/10.1111/1462-2920.14752DOI Listing
December 2019

Bioactivity and Mode of Action of Bacterial Tetramic Acids.

ACS Chem Biol 2019 08 11;14(8):1693-1697. Epub 2019 Jul 11.

Independent Junior Research Group Chemistry of Microbial Communication , Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI) , Beutenbergstrasse 11a , 07745 Jena , Germany.

Microbially produced 3-acyltetramic acids display a diverse range of biological activities. The pyreudiones are new members of this class that were isolated from bacteria of the genus . Here, we performed a structure-activity relationship study and determined their mode of action. An efficient biomimetic synthesis was developed to synthesize pyreudione A. Pyreudiones and synthetic analogs thereof were tested for their amoebicidal, antibacterial, antiproliferative, and cytotoxic activities. The length of the alkyl side chain and the nature of the amino acid residues within the tetramic acid moiety strongly affected activity, in particular against mycobacteria. The mode of action was shown to correlate with the ability of pyreudiones to act as protonophores. Removal of the acidic proton by methylation of pyreudione A resulted in a loss of bioactivity.
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http://dx.doi.org/10.1021/acschembio.9b00388DOI Listing
August 2019

Author Correction: Arylmethylamino steroids as antiparasitic agents.

Nat Commun 2019 Jul 8;10(1):2997. Epub 2019 Jul 8.

Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Heinrich Buff Ring 26-32, 35392, Giessen, Germany.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-11018-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614475PMC
July 2019

Biosynthesis of Diverse Antimicrobial and Antiproliferative Acyloins in Anaerobic Bacteria.

ACS Chem Biol 2019 07 21;14(7):1490-1497. Epub 2019 Jun 21.

Department of Biomolecular Chemistry , Leibniz Institute for Natural Product Research and Infection Biology (HKI) , Beutenbergstr. 11a , 07745 Jena , Germany.

Metabolic profiling and genome mining revealed that anaerobic bacteria have the potential to produce acyloin natural products. In addition to sattazolin A and B, three new sattazolin congeners and a novel acyloin named clostrocyloin were isolated from three strains of , a bacterium used for industrial solvent production. Bioactivity profiling showed that the sattazolin derivatives possess antimicrobial activities against mycobacteria and pseudomonads with only low cytotoxicity. Clostrocyloin was found to be mainly active against fungi. The thiamine diphosphate (ThDP)-dependent sattazolin-producing synthase was identified and characterized both and in enzyme assays. A related acyloin synthase from the clostrocyloin producer was shown to be responsible for the production of the acyloin core of clostrocyloin. The biotransformation experiments provided first insights into the substrate scope of the clostrocyloin synthase and revealed biosynthetic intermediates.
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http://dx.doi.org/10.1021/acschembio.9b00228DOI Listing
July 2019

Duckweed for Human Nutrition: No Cytotoxic and No Anti-Proliferative Effects on Human Cell Lines.

Plant Foods Hum Nutr 2019 Jun;74(2):223-224

Department of Plant Physiology, University of Jena, Jena, Germany.

Duckweeds (Lemnaceae) possess good qualitative and quantitative profiles of nutritional components for its use as human food. However, no studies have been conducted on the probable presence or absence of any adverse effects. The extracts from seven duckweed species (Spirodela polyrhiza, Landoltia punctata, Lemna gibba, Lemna minor, Wolffiella hyalina, Wolffia globosa, and Wolffia microscopica) covering all five genera of the plant family were herewith tested for cytotoxic effects on the human cell lines HUVEC, K-562, and HeLa and for anti-proliferative activity on HUVEC and K-562 cell lines. From these assays, it is evident that duckweeds do not possess any detectable anti-proliferative or cytotoxic effects, thus, the high nutritional value is not diminished by such detrimental factors. The present result is a first step to exclude any harmful effects of highly nutritious duckweed for human.
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http://dx.doi.org/10.1007/s11130-019-00725-xDOI Listing
June 2019

Formation of Nudicaulins In Vivo and In Vitro and the Biomimetic Synthesis and Bioactivity of -Methylated Nudicaulin Derivatives.

Molecules 2018 Dec 18;23(12). Epub 2018 Dec 18.

Max Planck Institute for Chemical Ecology, Hans-Knöll-Str. 8, D-07745 Jena, Germany.

Nudicaulins are yellow flower pigments accounting for the color of the petals of (Papaveraceae). These glucosidic compounds belong to the small group of indole/flavonoid hybrid alkaloids. Here we describe in vivo and in vitro experiments which substantiate the strongly pH-dependent conversion of pelargonidin glucosides to nudicaulins as the final biosynthetic step of these alkaloids. Furthermore, we report the first synthesis of nudicaulin aglycon derivatives, starting with quercetin and ending up at the biomimetic fusion of a permethylated anthocyanidin with indole. A small library of nudicaulin derivatives with differently substituted indole units was prepared, and the antimicrobial, antiproliferative and cell toxicity data of the new compounds were determined. The synthetic procedure is considered suitable for preparing nudicaulin derivatives which are structurally modified in the indole and/or the polyphenolic part of the molecule and may have optimized pharmacological activities.
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http://dx.doi.org/10.3390/molecules23123357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320756PMC
December 2018

Aspf2 From Recruits Human Immune Regulators for Immune Evasion and Cell Damage.

Front Immunol 2018 3;9:1635. Epub 2018 Aug 3.

Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Jena, Germany.

The opportunistic fungal pathogen can cause life-threatening infections, particularly in immunocompromised patients. Most pathogenic microbes control host innate immune responses at the earliest time, already before infiltrating host immune cells arrive at the site of infection. Here, we identify Aspf2 as the first Factor H-binding protein. Aspf2 recruits several human plasma regulators, Factor H, factor-H-like protein 1 (FHL-1), FHR1, and plasminogen. Factor H contacts Aspf2 two regions located in SCRs6-7 and SCR20. FHL-1 binds SCRs6-7, and FHR1 SCRs3-5. Factor H and FHL-1 attached to Aspf2-maintained cofactor activity and assisted in C3b inactivation. A Δ knockout strain was generated which bound Factor H with 28% and FHL-1 with 42% lower intensity. In agreement with less immune regulator acquisition, when challenged with complement-active normal human serum, Δ conidia had substantially more C3b (>57%) deposited on their surface. Consequently, Δ conidia were more efficiently phagocytosed (>20%) and killed (44%) by human neutrophils as wild-type conidia. Furthermore, Aspf2 recruited human plasminogen and, when activated by tissue-type plasminogen activator, newly generated plasmin cleaved the chromogenic substrate S2251 and degraded fibrinogen. Furthermore, plasmin attached to conidia damaged human lung epithelial cells, induced cell retraction, and caused matrix exposure. Thus, Aspf2 is a central immune evasion protein and plasminogen ligand of . By blocking host innate immune attack and by disrupting human lung epithelial cell layers, Aspf2 assists in early steps of fungal infection and likely allows tissue penetration.
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http://dx.doi.org/10.3389/fimmu.2018.01635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106110PMC
January 2019

Precursor-Directed Diversification of Cyclic Tetrapeptidic Pseudoxylallemycins.

Chembiochem 2018 11 4;19(21):2307-2311. Epub 2018 Oct 4.

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

Cyclic peptides containing non-proteinogenic amino acids often exhibit a broad bioactivity spectrum and many have entered clinical trials with good prospects for drug development. We recently reported the discovery of six cyclic tetrapeptides, pseudoxylallemycins A-F (1-6), from a termite-associated Pseudoxylaria sp. X802. These compounds contain a rare O-homoallenyl-l-tyrosine moiety and show promising antimicrobial activity against the Gram-negative pathogenic bacterium Pseudomonas aeruginosa. To perform more detailed structure-activity studies, we pursued a precursor-directed diversification strategy. Herein, we report the purification, identification, and testing of 21 new pseudoxylallemycin derivatives.
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http://dx.doi.org/10.1002/cbic.201800503DOI Listing
November 2018

Antitubercular and Cytotoxic Chlorinated seco-Cyclohexenes from Uvaria alba.

J Nat Prod 2017 12 27;80(12):3319-3323. Epub 2017 Nov 27.

Plant Sciences Laboratory, Research Center for the Natural and Applied Sciences, University of Santo Tomas , 1015 Manila, Philippines.

Two new chlorine-containing polyoxygenated seco-cyclohexenes, albanols A (1) and B (2), along with the oxepinone metabolite grandiuvarone (3) were isolated from the endemic Philippine Annonaceae plant Uvaria alba. Both new compounds exhibited modest antitubercular activity. Compound 1 showed cytostatic activity (ranging from 1-50 μM) against HeLa cells and weak antiproliferative activity against HUVEC and K-562 cells with GI values of 106 and 81 μM, respectively.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00679DOI Listing
December 2017

Streptococcus pneumoniae From Patients With Hemolytic Uremic Syndrome Binds Human Plasminogen via the Surface Protein PspC and Uses Plasmin to Damage Human Endothelial Cells.

J Infect Dis 2018 01;217(3):358-370

Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany.

Pneumococcal hemolytic uremic syndrome (HUS) in children is caused by infections with Streptococcus pneumoniae. Because endothelial cell damage is a hallmark of HUS, we studied how HUS-inducing pneumococci derived from infant HUS patients during the acute phase disrupt the endothelial layer. HUS pneumococci efficiently bound human plasminogen. These clinical isolates of HUS pneumococci efficiently bound human plasminogen via the bacterial surface proteins Tuf and PspC. When activated to plasmin at the bacterial surface, the active protease degraded fibrinogen and cleaved C3b. Here, we show that PspC is a pneumococcal plasminogen receptor and that plasmin generated on the surface of HUS pneumococci damages endothelial cells, causing endothelial retraction and exposure of the underlying matrix. Thus, HUS pneumococci damage endothelial cells in the blood vessels and disturb local complement homeostasis. Thereby, HUS pneumococci promote a thrombogenic state that drives HUS pathology.
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http://dx.doi.org/10.1093/infdis/jix305DOI Listing
January 2018

Isolation, Biosynthesis and Chemical Modifications of Rubterolones A-F: Rare Tropolone Alkaloids from Actinomadura sp. 5-2.

Chemistry 2017 Jul 21;23(39):9338-9345. Epub 2017 Jun 21.

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

The discovery of six new, highly substituted tropolone alkaloids, rubterolones A-F, from Actinomadura sp. 5-2, isolated from the gut of the fungus-growing termite Macrotermes natalensis is reported. Rubterolones were identified by using fungus-bacteria challenge assays and a HRMS-based dereplication strategy, and characterised by NMR and HRMS analyses and by X-ray crystallography. Feeding experiments and subsequent chemical derivatisation led to a first library of rubterolone derivatives (A-L). Genome sequencing and comparative analyses revealed their putative biosynthetic pathway, which was supported by feeding experiments. This study highlights how gut microbes can present a prolific source of secondary metabolites.
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http://dx.doi.org/10.1002/chem.201701005DOI Listing
July 2017

A tale of four kingdoms - isoxazolin-5-one- and 3-nitropropanoic acid-derived natural products.

Nat Prod Rep 2017 04;34(4):343-360

Department of Bioorganic Chemistry, Max Planck Institute for Chemical Ecology, Jena, Germany.

Covering up to September 2016This review reports on natural compounds that derive from the isoxazolinone ring as well as the 3-nitropropanoic acid (3-NPA) moiety. These structural elements occur in compounds that have been identified in plants, insects, bacteria and fungi. In particular, plants belonging to the family of legumes produce such compounds. In the case of insects, isoxazolin-5-one and 3-NPA derivatives were found in leaf beetles of the subtribe Chrysomelina. A number of these natural products have been synthesized so far. In the case of the single compound 3-NPA, several synthetic strategies have been reported and some of the most efficient routes are reviewed. The toxicity of 3-NPA results from its ability to bind covalently to the catalytic center of succinate dehydrogenase causing irreversible inhibition of mitochondrial respiration. As a motif that is produced by many species of plants, leaf beetles and fungi, different detoxification mechanisms for 3-NPA have evolved in different species. These mechanisms are based on amide formation of 3-NPA with amino acids, reduction to β-alanine, ester formation or oxidation to malonic acid semialdehyde. The biosynthetic pathways of 3-NPA and isoxazolin-5-one moieties have been studied in fungi, plants and leaf beetles. In the case of fungi, 3-NPA derives from aspartate, while leaf beetles use essential amino acids such as valine as ultimate precursors. In the case of plants, it is supposed that malonate serves as a precursor of 3-NPA, as indicated by feeding of C-labeled precursors to Indigofera spicata. In other leguminous plants it is suggested that asparagine is incorporated into compounds that derive from isoxazolin-5-one, which was indicated by C-labeled compounds as well. In the case of leaf beetles it was demonstrated that detection of radioactivity after C-labeling from a few precursors is not sufficient to unravel biosynthetic pathways.
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http://dx.doi.org/10.1039/c6np00122jDOI Listing
April 2017

Arylmethylamino steroids as antiparasitic agents.

Nat Commun 2017 02 17;8:14478. Epub 2017 Feb 17.

Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Heinrich Buff Ring 26-32, 35392 Giessen, Germany.

In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. The lead compound 1o is fast acting and highly active against intraerythrocytic stages of chloroquine-sensitive and resistant Plasmodium falciparum parasites (IC 1-5 nM) as well as against gametocytes. In P. berghei-infected mice, oral administration of 1o drastically reduces parasitaemia and cures the animals. Furthermore, 1o efficiently blocks parasite transmission from mice to mosquitoes. The steroid compounds show low cytotoxicity in mammalian cells and do not induce acute toxicity symptoms in mice. Moreover, 1o has a remarkable activity against the blood-feeding trematode parasite Schistosoma mansoni. The steroid and the hydroxyarylmethylamino moieties are essential for antimalarial activity supporting a chelate-based quinone methide mechanism involving metal or haem bioactivation. This study identifies chemical scaffolds that are rapidly internalized into blood-feeding parasites.
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http://dx.doi.org/10.1038/ncomms14478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321741PMC
February 2017

Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator.

J Neuroinflammation 2017 01 5;14(1). Epub 2017 Jan 5.

Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Beutenbergstrasse 11, 07745, Jena, Germany.

Background: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The polymorphism rs10490924 in the ARMS2 gene is highly associated with AMD and linked to an indel mutation (del443ins54), the latter inducing mRNA instability. At present, the function of the ARMS2 protein, the exact cellular sources in the retina and the biological consequences of the rs10490924 polymorphism are unclear.

Methods: Recombinant ARMS2 was expressed in Pichia pastoris, and protein functions were studied regarding cell surface binding and complement activation in human serum using fluoresence-activated cell sorting (FACS) as well as laser scanning microscopy (LSM). Biolayer interferometry defined protein interactions. Furthermore, endogenous ARMS2 gene expression was studied in human blood derived monocytes and in human induced pluripotent stem cell-derived microglia (iPSdM) by PCR and LSM. The ARMS2 protein was localized in human genotyped retinal sections and in purified monocytes derived from AMD patients without the ARMS2 risk variant by LSM. ARMS2 expression in monocytes under oxidative stress was determined by Western blot analysis.

Results: Here, we demonstrate for the first time that ARMS2 functions as surface complement regulator. Recombinant ARMS2 binds to human apoptotic and necrotic cells and initiates complement activation by recruiting the complement activator properdin. ARMS2-properdin complexes augment C3b surface opsonization for phagocytosis. We also demonstrate for the first time expression of ARMS2 in human monocytes especially under oxidative stress and in microglia cells of the human retina. The ARMS2 protein is absent in monocytes and also in microglia cells, derived from patients homozygous for the ARMS2 AMD risk variant (rs10490924).

Conclusions: ARMS2 is likely involved in complement-mediated clearance of cellular debris. As AMD patients present with accumulated proteins and lipids on Bruch's membrane, ARMS2 protein deficiency due to the genetic risk variant might be involved in drusen formation.
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http://dx.doi.org/10.1186/s12974-016-0776-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234120PMC
January 2017

Pseudoxylallemycins A-F, Cyclic Tetrapeptides with Rare Allenyl Modifications Isolated from Pseudoxylaria sp. X802: A Competitor of Fungus-Growing Termite Cultivars.

Org Lett 2016 07 24;18(14):3338-41. Epub 2016 Jun 24.

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

Based on fungus-fungus pairing assays and HRMS-based dereplication strategy, six new cyclic tetrapeptides, pseudoxylallemycins A-F (1-6), were isolated from the termite-associated fungus Pseudoxylaria sp. X802. Structures were characterized using NMR spectroscopy, HRMS, and Marfey's reaction. Pseudoxylallemycins B-D (2-4) possess a rare and chemically accessible allene moiety amenable for synthetic modifications, and derivatives A-D showed antimicrobial activity against Gram-negative human-pathogenic Pseudomonas aeruginosa and antiproliferative activity against human umbilical vein endothelial cells and K-562 cell lines.
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http://dx.doi.org/10.1021/acs.orglett.6b01437DOI Listing
July 2016

Bipiperidine conjugates as soluble sugar surrogates in DNA-intercalating antiproliferative polyketides.

Chem Commun (Camb) 2016 Apr 14;52(27):4894-7. Epub 2016 Mar 14.

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

DNA-intercalating polyketide glycosides are important leads for cancer therapeutics, yet their use is often limited by their low solubility and challenging synthetic protocols. To overcome these limitations, we employed 1,4'-bipiperidine-1'-carbamate residues as sugar surrogates in daunorubicin and chartreusin, yielding water-soluble derivatives and prodrugs with dramatically improved antiproliferative activities.
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http://dx.doi.org/10.1039/c6cc00890aDOI Listing
April 2016

Plant pathogenic anaerobic bacteria use aromatic polyketides to access aerobic territory.

Science 2015 Nov;350(6261):670-4

Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany. Department of Natural Product Chemistry, Friedrich Schiller University, Jena, Germany.

Around 25% of vegetable food is lost worldwide because of infectious plant diseases, including microbe-induced decay of harvested crops. In wet seasons and under humid storage conditions, potato tubers are readily infected and decomposed by anaerobic bacteria (Clostridium puniceum). We found that these anaerobic plant pathogens harbor a gene locus (type II polyketide synthase) to produce unusual polyketide metabolites (clostrubins) with dual functions. The clostrubins, which act as antibiotics against other microbial plant pathogens, enable the anaerobic bacteria to survive an oxygen-rich plant environment.
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http://dx.doi.org/10.1126/science.aac9990DOI Listing
November 2015

Harnessing Enzymatic Promiscuity in Myxochelin Biosynthesis for the Production of 5-Lipoxygenase Inhibitors.

Chembiochem 2015 Nov 13;16(17):2445-50. Epub 2015 Oct 13.

Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Adolf-Reichwein-Strasse 23, 07745, Jena, Germany.

The siderophore myxochelin A is a potent inhibitor of human 5-lipoxygenase (5-LO). To clarify whether the iron-chelating properties of myxochelin A are responsible for this activity, several analogues of this compound were generated in the native producer Pyxidicoccus fallax by precursor-directed biosynthesis. Testing in a cell-free assay unveiled three derivatives with bioactivity comparable with that of myxochelin A. Furthermore, it became evident that inhibition of 5-LO by myxochelins does not correlate with their iron affinities.
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http://dx.doi.org/10.1002/cbic.201500446DOI Listing
November 2015

Identification of the antiphagocytic trypacidin gene cluster in the human-pathogenic fungus Aspergillus fumigatus.

Appl Microbiol Biotechnol 2015 Dec 18;99(23):10151-61. Epub 2015 Aug 18.

Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Beutenbergstrasse 11a, 07745, Jena, Germany.

The opportunistic human pathogen Aspergillus fumigatus produces numerous different natural products. The genetic basis for the biosynthesis of a number of known metabolites has remained unknown. The gene cluster encoding for the biosynthesis of the conidia-bound metabolite trypacidin is of particular interest because of its antiprotozoal activity and possible role in the infection process. Here, we show that the genes encoding the biosynthesis enzymes of trypacidin reside within an orphan gene cluster in A. fumigatus. Genome mining identified tynC as an uncharacterized polyketide synthase with high similarity to known enzymes, whose products are structurally related to trypacidin including endocrocin and fumicycline. Gene deletion of tynC resulted in the complete absence of trypacidin production, which was fully restored when the mutant strain was complemented with the wild-type gene. When confronted with macrophages, the tynC deletion mutant conidia were more frequently phagocytosed than those of the parental wild-type strain. This was also found for phagocytic amoebae of the species Dictyostelium discoideum, which showed increased phagocytosis of ΔtynC conidia. Both macrophages and amoebae were also sensitive to trypacidin. Therefore, our results suggest that the conidium-bound trypacidin could have a protective function against phagocytes both in the environment and during the infection process.
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http://dx.doi.org/10.1007/s00253-015-6898-1DOI Listing
December 2015
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