• Labyrinthopeptins exert broad-spectrum antiviral activity through lipid-binding-mediated virolysis.

      Prochnow, Hans; Rox, Katharina; Birudukota, N V Suryanarayana; Weichert, Loreen; Hotop, Sven-Kevin; Klahn, Philipp; Mohr, Kathrin; Franz, Sergej; Banda, Dominic H; Blockus, Sebastian; et al. (ASM, 2019-10-30)
      To counteract the serious health threat posed by known and novel viral pathogens, drugs that target a variety of viruses through a common mechanism have attracted recent attention due to their potential in treating (re-)emerging infections, for which direct acting antivirals are not available. We found that labyrinthopeptins A1 and A2, the prototype congeners of carbacyclic lanthipeptides, inhibit the proliferation of diverse enveloped viruses, including Dengue virus, Zika virus, West Nile virus, Hepatitis C virus, Chikungunya virus, Karposi's Sarcoma-associated Herpes virus, Cytomegalovirus, and Herpes Simplex virus, in the low μM to nM range. Mechanistic studies on viral particles revealed that labyrinthopeptins induce a virolytic effect through binding to the viral membrane lipid phosphatidylethanolamine (PE). These effects are enhanced by a combined equimolar application of both labyrinthopeptins, and a clear synergism was observed across a concentration range corresponding to IC10-IC90 values of the compounds. Time-resolved experiments with large unilamellar vesicles (LUVs) reveal that membrane lipid raft compositions (PC/PE/Chol/SM (17:10:33:40)) are particularly sensitive to labyrinthopeptins compared to PC/PE (90:10) LUVs, even though the overall PE-amount remains constant. Labyrinthopeptins exhibited low cytotoxicity and had favorable pharmacokinetic properties in mice (t1/2= 10.0 h), which designates them as promising antiviral compounds acting by an unusual viral lipid targeting mechanism.Importance For many viral infections, current treatment options are insufficient. Because the development of each antiviral drug is time-consuming and expensive, the prospect of finding broad-spectrum antivirals that can fight multiple, diverse viruses - well-known as well as (re-)emerging species - has gained attention, especially for the treatment of viral co-infections. While most known broad spectrum agents address processes in the host cell, we found that targeting lipids of the free virus outside the host cell with the natural products labyrinthopeptin A1 and A2 is a viable strategy to inhibit the proliferation of a broad range of viruses from different families, including Chikungunya virus, Dengue virus, Zika virus, Karposi's Sarcoma-associated Herpes virus, or Cytomegalovirus. Labyrinthopeptins bind to viral phosphatidylethanolamine and induce virolysis without exerting cytotoxicity to host cells. This represents a novel and unusual mechanism to tackle medically relevant viral infections.
    • Sparticolins A-G, Biologically Active Oxidized Spirodioxynaphthalene Derivatives from the Ascomycete Sparticola junci.

      Phukhamsakda, Chayanard; Macabeo, Allan Patrick G; Huch, Volker; Cheng, Tian; Hyde, Kevin D; Stadler, Marc; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (American Society of Chemistry, 2019-10-25)
      To explore the chemical diversity of metabolites from new species of Dothideomycetes, the ex-type strain of Sparticola junci was investigated. Seven highly oxygenated and functionalized spirodioxynaphthalene natural products incorporating carboxyalkylidene-cyclopentanoid (1-4), carboxyl-functionalized oxabicyclo[3.3.0]octane (5-6), and annelated 2-cyclopentenone/δ-lactone (7) units, sparticolins A-G, were isolated from submerged cultures of the fungus. Their chemical structures including their relative (and absolute) configurations were established through spectroscopic and X-ray crystallographic analyses. Sparticolin B (2) exhibited inhibitory activity against the Gram-positive bacteria Bacillus subtilis, Micrococcus luteus, and Staphylococcus aureus, while sparticolin G (7) showed antifungal activities against Schizosaccharomyces pombe and Mucor hiemalis. All other sparticolins were only weakly active against S. aureus and also showed weak activities against the nematode Caenorhabditis elegans. Compounds 2 and 7 also showed moderate cytotoxic activities against seven mammalian cell lines.
    • Cytotoxic, anti-biofilm and antimicrobial polyketides from the plant associated fungus Chaetosphaeronema achilleae.

      Narmani, Abolfazl; Teponno, Rémy Bertrand; Helaly, Soleiman E; Arzanlou, Mahdi; Stadler, Marc; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Elsevier, 2019-10-23)
      From extracts of the plant associated fungus Chaetosphaeronema achilleae collected in Iran, a previously unreported isoindolinone named chaetosisoindolinone (1) and a previously undescribed indanone named chaetosindanone (2) were isolated in addition to five known metabolites, 2-(2-acetyl-3,5-dihydroxyphenyl) acetic acid (3), vulculic acid (4), 2-(2-acetyl-3-hydroxy-5-methoxyphenyl)acetic acid (5), curvulin (6), and curvulol (7). Their structures were elucidated on the basis of extensive spectroscopic analysis and high-resolution mass spectrometry. The isolated compounds were tested for their antimicrobial, anti-biofilm, and nematicidal activities. Compound 2 exhibited cytotoxicity against the human breast adenocarcinoma MCF-7 cells with an IC50 value of 1.5 μg/mL. Furthermore, compounds 4 and 7 almost completely inhibited biofilm formation in Staphylococcus aureus at 256 μg/mL. Weak antimicrobial activities were also observed for some of the isolated compounds against Mucor hiemalis, Rhodoturula glutinis, Chromobacterium violaceum, and Staphylococcus aureus.
    • Structurally diverse metabolites from the rare actinobacterium Saccharothrix xinjiangensis.

      Babadi, Zahra Khosravi; Sudarman, Enge; Ebrahimipour, Gholam Hossein; Primahana, Gian; Stadler, Marc; Wink, Joachim; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Japan Antibiotics Research Association, 2019-08-26)
      The bioassay-guided fractionation from cultures of the actinobacterium Saccharothrix xinjiangensis Act24Zk, collected from the Caspian Sea beach in Iran led to the isolation of three new compounds, caerulomycin M (1), saccharopyrone (2), and saccharonoic acid (3), together with the known compound, caerulomycin A (4). Their structures were elucidated from HR-ESIMS and 1D and 2D NMR data. Compound 2 displayed moderate cytotoxic activity against the human cervix carcinoma HeLa cells KB3.1 with an IC50 value of 5.4 µM.
    • The amazing potential of fungi: 50 ways we can exploit fungi industrially

      Hyde, Kevin D.; Xu, Jianchu; Rapior, Sylvie; Jeewon, Rajesh; Lumyong, Saisamorn; Niego, Allen Grace T.; Abeywickrama, Pranami D.; Aluthmuhandiram, Janith V.S.; Brahamanage, Rashika S.; Brooks, Siraprapa; et al. (Springer, 2019-07-31)
      Fungi are an understudied, biotechnologically valuable group of organisms. Due to the immense range of habitats that fungi inhabit, and the consequent need to compete against a diverse array of other fungi, bacteria, and animals, fungi have developed numerous survival mechanisms. The unique attributes of fungi thus herald great promise for their application in biotechnology and industry. Moreover, fungi can be grown with relative ease, making production at scale viable. The search for fungal biodiversity, and the construction of a living fungi collection, both have incredible economic potential in locating organisms with novel industrial uses that will lead to novel products. This manuscript reviews fifty ways in which fungi can potentially be utilized as biotechnology. We provide notes and examples for each potential exploitation and give examples from our own work and the work of other notable researchers. We also provide a flow chart that can be used to convince funding bodies of the importance of fungi for biotechnological research and as potential products. Fungi have provided the world with penicillin, lovastatin, and other globally significant medicines, and they remain an untapped resource with enormous industrial potential.
    • Current insights into fungal species diversity and perspective on naming the environmental DNA sequences of fungi

      Wu, Bing; Hussain, Muzammil; Zhang, Weiwei; Stadler, Marc; Liu, Xingzhong; Xiang, Meichun; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Taylor&Francis, 2019-07-03)
      The global bio-diversity of fungi has been extensively investigated and their species number has been estimated. Notably, the development of molecular phylogeny has revealed an unexpected fungal diversity and utilisation of culture-independent approaches including high-throughput amplicon sequencing has dramatically increased number of fungal operational taxonomic units. A number of novel taxa including new divisions, classes, orders and new families have been established in last decade. Many cryptic species were identified by molecular phylogeny. Based on recently generated data from culture-dependent and -independent survey on same samples, the fungal species on the earth were estimated to be 12 (11.7–13.2) million compared to 2.2–3.8 million species recently estimated by a variety of the estimation techniques. Moreover, it has been speculated that the current use of high-throughput sequencing techniques would reveal an even higher diversity than our current estimation. Recently, the formal classification of environmental sequences and permission of DNA sequence data as fungal names’ type were proposed but strongly objected by the mycologist community. Surveys on fungi in unusual niches have indicated that many previously regarded “unculturable fungi” could be cultured on certain substrates under specific conditions. Moreover, the high-throughput amplicon sequencing, shotgun metagenomics and a single-cell genomics could be a powerful means to detect novel taxa. Here, we propose to separate the fungal types into physical type based on specimen, genome DNA (gDNA) type based on complete genome sequence of culturable and uncluturable fungal specimen and digital type based on environmental DNA sequence data. The physical and gDNA type should have priority, while the digital type can be temporal supplementary before the physical type and gDNA type being available. The fungal name based on the “digital type” could be assigned as the “clade” name + species name. The “clade” name could be the name of genus, family or order, etc. which the sequence of digital type affiliates to. Facilitating future cultivation efforts should be encouraged. Also, with the advancement in knowledge of fungi inhabiting various environments mostly because of rapid development of new detection technologies, more information should be expected for fungal diversity on our planet. © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
    • The nuclear export inhibitor aminoratjadone is a potent effector in extracellular-targeted drug conjugates.

      Klahn, Philipp; Fetz, Verena; Ritter, Antje; Collisi, Wera; Hinkelmann, Bettina; Arnold, Tatjana; Tegge, Werner; Rox, Katharina; Hüttel, Stephan; Mohr, Kathrin I; et al. (Royal Society of Chemistry, 2019-05-28)
      The concept of targeted drug conjugates has been successfully translated to clinical practice in oncology. Whereas the majority of cytotoxic effectors in drug conjugates are directed against either DNA or tubulin, our study aimed to validate nuclear export inhibition as a novel effector principle in drug conjugates. For this purpose, a semisynthetic route starting from the natural product ratjadone A, a potent nuclear export inhibitor, has been developed. The biological evaluation of ratjadones functionalized at the 16-position revealed that oxo- and amino-analogues had very high potencies against cancer cell lines (e.g. 16R-aminoratjadone 16 with IC50 = 260 pM against MCF-7 cells, or 19-oxoratjadone 14 with IC50 = 100 pM against A-549 cells). Mechanistically, the conjugates retained a nuclear export inhibitory activity through binding CRM1. To demonstrate a proof-of-principle for cellular targeting, folate- and luteinizing hormone releasing hormone (LHRH)-based carrier molecules were synthesized and coupled to aminoratjadones as well as fluorescein for cellular efficacy and imaging studies, respectively. The Trojan-Horse conjugates selectively addressed receptor-positive cell lines and were highly potent inhibitors of their proliferation. For example, the folate conjugate FA-7-Val-Cit-pABA-16R-aminoratjadone had an IC50 of 34.3 nM, and the LHRH conjugate d-Orn-Gose-Val-Cit-pABA-16R-aminoratjadone had an IC50 of 12.8 nM. The results demonstrate that nuclear export inhibition is a promising mode-of-action for extracellular-targeted drug conjugate payloads.
    • Kenalactams A-E, Polyene Macrolactams Isolated from Nocardiopsis CG3.

      Messaoudi, Omar; Sudarman, Enge; Bendahou, Mourad; Jansen, Rolf; Stadler, Marc; Wink, Joachim; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (American Cemical Society (ACS), 2019-05-24)
      In our screening program for new biologically active secondary metabolites, a new strain, Nocardiopsis CG3 (DSM 106572), isolated from the saltpan of Kenadsa, was found to produce five new polyene macrolactams, the kenalactams A-E (1-5). Their structures were elucidated by spectral methods (NMR and HRESIMS), and the absolute configuration was derived by chemical derivatization (Mosher's method). Through a feeding experiment, alanine was proven to be the nitrogen-bearing starter unit involved in biosynthesis of the polyketide kenalactam A (1). Kenalactam E (5) was cytotoxic against human prostate cancer PC-3 cells with an IC50 value of 2.1 μM.
    • Sesquiterpenes from an Eastern African Medicinal Mushroom Belonging to the Genus Sanghuangporus.

      Cheng, Tian; Chepkirui, Clara; Decock, Cony; Matasyoh, Josphat Clement; Stadler, Marc; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (American Cemical Society (ACS), 2019-05-24)
      During the course of searching for new anti-infective and other biologically active secondary metabolites from Kenyan basidiomycetes, 13 previously undescribed metabolites, (6 R,7 S,10 R)-7,10-epoxy-7,11-dimethyldodec-1-ene-6,11-diol (1) and 12 sesquiterpenes named elgonenes A-L (2-13), and the known compound P-coumaric acid (14) were isolated from a basidiomycete collected in Mount Elgon Natural Reserve. The producing organism represents a new species of the genus Sanghuangporus, which is one of the segregates of the important traditional Asian medicinal mushrooms that were formerly known as the " Inonotus linteus" complex. The structure elucidation of compounds 1-13, based on 2D NMR spectroscopy, high-resolution mass spectrometry, and other spectral methods, and their antibacterial, antifungal, and cytotoxic activities are reported.
    • Antiviral Meroterpenoid Rhodatin and Sesquiterpenoids Rhodocoranes A-E from the Wrinkled Peach Mushroom, Rhodotus palmatus.

      Sandargo, Birthe; Michehl, Maira; Praditya, Dimas; Steinmann, Eike; Stadler, Marc; Surup, Frank; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany. (American Chemical Society, 2019-05-03)
      Rhodatin (1), a meroterpenoid featuring a unique pentacyclic scaffold with both spiro and spiroketal centers, and five unusual acorane-type sesquiterpenoids, named rhodocoranes A-E (2-6, respectively), are the first natural products isolated from the basidiomycete Rhodotus palmatus. Their structures were elucidated by two-dimensional NMR experiments and HRESIMS, while the absolute configuration of the substance family was determined by Mosher's method utilizing 2. Rhodatin strongly inhibited hepatitis C virus, whereas 4 displayed cytotoxicity and selective antifungal activity.
    • Fungal diversity notes 929–1035: taxonomic and phylogenetic contributions on genera and species of fungi

      Phookamsak, Rungtiwa; Stadler, Mark; et al.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Springer-Nature, 2019-05-01)
      This article is the ninth in the series of Fungal Diversity Notes, where 107 taxa distributed in three phyla, nine classes, 31 orders and 57 families are described and illustrated. Taxa described in the present study include 12 new genera, 74 new species, three new combinations, two reference specimens, a re-circumscription of the epitype, and 15 records of sexual-asexual morph connections, new hosts and new geographical distributions. Twelve new genera comprise Brunneofusispora, Brunneomurispora, Liua, Lonicericola, Neoeutypella, Paratrimmatostroma, Parazalerion, Proliferophorum, Pseudoastrosphaeriellopsis, Septomelanconiella, Velebitea and Vicosamyces. Seventy-four new species are Agaricus memnonius, A. langensis, Aleurodiscus patagonicus, Amanita flavoalba, A. subtropicana, Amphisphaeria mangrovei, Baorangia major, Bartalinia kunmingensis, Brunneofusispora sinensis, Brunneomurispora lonicerae, Capronia camelliae-yunnanensis, Clavulina thindii, Coniochaeta simbalensis, Conlarium thailandense, Coprinus trigonosporus, Liua muriformis, Cyphellophora filicis, Cytospora ulmicola, Dacrymyces invisibilis, Dictyocheirospora metroxylonis, Distoseptispora thysanolaenae, Emericellopsis koreana, Galiicola baoshanensis, Hygrocybe lucida, Hypoxylon teeravasati, Hyweljonesia indica, Keissleriella caraganae, Lactarius olivaceopallidus, Lactifluus midnapurensis, Lembosia brigadeirensis, Leptosphaeria urticae, Lonicericola hyaloseptispora, Lophiotrema mucilaginosis, Marasmiellus bicoloripes, Marasmius indojasminodorus, Micropeltis phetchaburiensis, Mucor orantomantidis, Murilentithecium lonicerae, Neobambusicola brunnea, Neoeutypella baoshanensis, Neoroussoella heveae, Neosetophoma lonicerae, Ophiobolus malleolus, Parabambusicola thysanolaenae, Paratrimmatostroma kunmingensis, Parazalerion indica, Penicillium dokdoense, Peroneutypa mangrovei, Phaeosphaeria cycadis, Phanerochaete australosanguinea, Plectosphaerella kunmingensis, Plenodomus artemisiae, P. lijiangensis, Proliferophorum thailandicum, Pseudoastrosphaeriellopsis kaveriana, Pseudohelicomyces menglunicus, Pseudoplagiostoma mangiferae, Robillarda mangiferae, Roussoella elaeicola, Russula choptae, R. uttarakhandia, Septomelanconiella thailandica, Spencermartinsia acericola, Sphaerellopsis isthmospora, Thozetella lithocarpi, Trechispora echinospora, Tremellochaete atlantica, Trichoderma koreanum, T. pinicola, T. rugulosum, Velebitea chrysotexta, Vicosamyces venturisporus, Wojnowiciella kunmingensis and Zopfiella indica. Three new combinations are Baorangia rufomaculata, Lanmaoa pallidorosea and Wojnowiciella rosicola. The reference specimens of Canalisporium kenyense and Tamsiniella labiosa are designated. The epitype of Sarcopeziza sicula is re-circumscribed based on cyto- and histochemical analyses. The sexual-asexual morph connection of Plenodomus sinensis is reported from ferns and Cirsium for the first time. In addition, the new host records and country records are Amanita altipes, A. melleialba, Amarenomyces dactylidis, Chaetosphaeria panamensis, Coniella vitis, Coprinopsis kubickae, Dothiorella sarmentorum, Leptobacillium leptobactrum var. calidus, Muyocopron lithocarpi, Neoroussoella solani, Periconia cortaderiae, Phragmocamarosporium hederae, Sphaerellopsis paraphysata and Sphaeropsis eucalypticola.
    • A novel species and a new combination of Daldinia from Ban Hua Thung community forest in the northern part of Thailand

      Wongkanoun, Sarunyou; Wendt, Lucile; Stadler, Marc; Luangsa-ard, Jennifer; Srikitikulchai, Prasert; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Springer, 2019-04-02)
      During a survey of Xylariales in northern Thailand, several specimens with affinities to the genus Daldinia were found and examined for morphological characters, secondary metabolites, and molecular phylogenetic traits. Aside from morphological and chemotaxonomic studies, a multi-locus phylogenetic analysis using internal transcribed spacers regions (ITS) and the large subunit (LSU) of the ribosomal DNA, the second largest subunit of the RNA polymerase (RPB2), and beta-tubulin (TUB2) genes was performed. Among the specimens was a new species and a new record of a species that had previously never been sequenced and studied for its anamorphic morphology. This species, previously described by Ju and Rogers as Hypoxylon kretzschmarioides based on a single record from Indonesia, showed secondary metabolite profiles reminiscent of those of the genus Daldinia and even clustered in the latter genus in the phylogenetic tree. Therefore, it is transferred to Daldinia as D. kretzschmarioides comb. nov. A second new species, D. subvernicosa sp. nov., was found to have a close relationship with D. vernicosa based on morphological and molecular evidence, but differs from D. vernicosa by long-stipitate asci with mostly subglobose ascospores, and the basal ascospores are often elongated.
    • Cytotoxic, antimicrobial and antiviral secondary metabolites produced by the plant pathogenic fungus Cytospora sp. CCTU A309.

      Narmani, Abolfazl; Teponno, Rémy Bertrand; Arzanlou, Mahdi; Surup, Frank; Helaly, Soleiman E; Wittstein, Kathrin; Praditya, Dimas F; Babai-Ahari, Asadollah; Steinmann, Eike; Stadler, Marc; et al. (Elsevier, 2019-04-01)
      Chemical analysis of extracts from cultures of the plant pathogenic fungus Cytospora sp. strain CCTU A309 collected in Iran led to the isolation of two previously unreported heptanedioic acid derivatives namely (2R,3S) 2-hydroxy-3-phenyl-4-oxoheptanedioic acid (1) and (2S,3S) 2-hydroxy-3-phenyl-4-oxoheptanedioic acid (2) as diastereomers, four previously undescribed prenylated p-terphenyl quinones 3-6 in addition to five known metabolites. Their structures were elucidated on the basis of extensive spectroscopic analysis and high-resolution mass spectrometry. For metabolites 1 and 2, the absolute configurations at C-2 were deduced from comparison of the 1H NMR difference of their (S)- and (R)-phenylglycine methyl ester derivatives while the relative configurations were tentatively assigned by a J-based analysis and confirmed by comparison of 13C chemical shifts to literature data. The isolated compounds were tested for their cytotoxic, antimicrobial (including biofilm inhibition), antiviral, and nematicidal activities. While only moderate antimicrobial effects were observed, the terphenyl quinone derivatives 3-6 and leucomelone (10) exhibited significant cytotoxicity against the mouse fibroblast L929 and cervix carcinoma KB-3-1 cell lines with IC50 values ranging from 2.4 to 26 μg/mL. Furthermore, metabolites 4-6 showed interesting antiviral activity against hepatitis C virus (HCV).
    • Cystobactamids 920-1 and 920-2: Assignment of the Constitution and Relative Configuration by Total Synthesis.

      Planke, Therese; Moreno, María; Hüttel, Stephan; Fohrer, Jörg; Gille, Franziska; Norris, Matthew D; Siebke, Maik; Wang, Liangliang; Müller, Rolf; Kirschning, Andreas; et al. (ACS Publications, 2019-03-01)
      Total synthesis of cystobactamid 920-1 and its epimer has allowed an unambiguous assignment of the relative and absolute configuration of the natural product. A careful structural analysis of each isomer using both NMR and computational techniques also prompted a constitutional revision of the structures originally reported for cystobactamids 920-1 and 920-2, and has provided further insight into the unique conformational preferences of the cystobactamid family
    • The Effect of Cytochalasans on the Actin Cytoskeleton of Eukaryotic Cells and Preliminary Structure⁻Activity Relationships.

      Kretz, Robin; Wendt, Lucile; Wongkanoun, Sarunyou; Luangsa-Ard, J Jennifer; Surup, Frank; Helaly, Soleiman E; Noumeur, Sara R; Stadler, Marc; Stradal, Theresia E B; HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig Germany. (MDPI, 2019-02-19)
      In our ongoing search for new bioactive fungal metabolites, two new cytochalasans were isolated from stromata of the hypoxylaceous ascomycete Hypoxylon fragiforme. Their structures were elucidated via high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy. Together with 23 additional cytochalasans isolated from ascomata and mycelial cultures of different Ascomycota, they were tested on their ability to disrupt the actin cytoskeleton of mammal cells in a preliminary structure⁻activity relationship study. Out of all structural features, the presence of hydroxyl group at the C7 and C18 residues, as well as their stereochemistry, were determined as important factors affecting the potential to disrupt the actin cytoskeleton. Moreover, reversibility of the actin disrupting effects was tested, revealing no direct correlations between potency and reversibility in the tested compound group. Since the diverse bioactivity of cytochalasans is interesting for various applications in eukaryotes, the exact effect on eukaryotic cells will need to be determined, e.g., by follow-up studies involving medicinal chemistry and by inclusion of additional natural cytochalasans. The results are also discussed in relation to previous studies in the literature, including a recent report on the anti-Biofilm activities of essentially the same panel of compounds against the pathogenic bacterium, Staphylococcus aureus.
    • The Effect of Cytochalasans on the Actin Cytoskeleton of Eukaryotic Cells and Preliminary Structure⁻Activity Relationships.

      Kretz, Robin; Wendt, Lucile; Wongkanoun, Sarunyou; Luangsa-Ard, J Jennifer; Surup, Frank; Helaly, Soleiman E; Noumeur, Sara R; Stadler, Marc; Stradal, Theresia E B; HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig Germany. (MPDI, 2019-02-19)
      In our ongoing search for new bioactive fungal metabolites, two new cytochalasans were isolated from stromata of the hypoxylaceous ascomycete Hypoxylon fragiforme. Their structures were elucidated via high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy. Together with 23 additional cytochalasans isolated from ascomata and mycelial cultures of different Ascomycota, they were tested on their ability to disrupt the actin cytoskeleton of mammal cells in a preliminary structure–activity relationship study. Out of all structural features, the presence of hydroxyl group at the C7 and C18 residues, as well as their stereochemistry, were determined as important factors affecting the potential to disrupt the actin cytoskeleton. Moreover, reversibility of the actin disrupting effects was tested, revealing no direct correlations between potency and reversibility in the tested compound group. Since the diverse bioactivity of cytochalasans is interesting for various applications in eukaryotes, the exact effect on eukaryotic cells will need to be determined, e.g., by follow-up studies involving medicinal chemistry and by inclusion of additional natural cytochalasans. The results are also discussed in relation to previous studies in the literature, including a recent report on the anti-Biofilm activities of essentially the same panel of compounds against the pathogenic bacterium, Staphylococcus aureus. View Full-Text
    • Structures of an RNA polymerase promoter melting intermediate elucidate DNA unwinding.

      Boyaci, Hande; Chen, James; Jansen, Rolf; Darst, Seth A; Campbell, Elizabeth A; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Nature publishing group, 2019-01-09)
      A key regulated step of transcription is promoter melting by RNA polymerase (RNAP) to form the open promoter complex
    • An endothelial cell line infected by Kaposi's sarcoma-associated herpes virus (KSHV) allows the investigation of Kaposi's sarcoma and the validation of novel viral inhibitors in vitro and in vivo.

      Dubich, Tatyana; Lieske, Anna; Santag, Susann; Beauclair, Guillaume; Rückert, Jessica; Herrmann, Jennifer; Gorges, Jan; Büsche, Guntram; Kazmaier, Uli; Hauser, Hansjörg; et al. (2019-01-04)
      Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), a tumor of endothelial origin predominantly affecting immunosuppressed individuals. Up to date, vaccines and targeted therapies are not available. Screening and identification of anti-viral compounds are compromised by the lack of scalable cell culture systems reflecting properties of virus-transformed cells in patients. Further, the strict specificity of the virus for humans limits the development of in vivo models. In this study, we exploited a conditionally immortalized human endothelial cell line for establishment of in vitro 2D and 3D KSHV latency models and the generation of KS-like xenograft tumors in mice. Importantly, the invasive properties and tumor formation could be completely reverted by purging KSHV from the cells, confirming that tumor formation is dependent on the continued presence of KSHV, rather than being a consequence of irreversible transformation of the infected cells. Upon testing a library of 260 natural metabolites, we selected the compounds that induced viral loss or reduced the invasiveness of infected cells in 2D and 3D endothelial cell culture systems. The efficacy of selected compounds against KSHV-induced tumor formation was verified in the xenograft model. Together, this study shows that the combined use of anti-viral and anti-tumor assays based on the same cell line is predictive for tumor reduction in vivo and therefore allows faithful selection of novel drug candidates against Kaposi's sarcoma. KEY MESSAGES: Novel 2D, 3D, and xenograft mouse models mimic the consequences of KSHV infection. KSHV-induced tumorigenesis can be reverted upon purging the cells from the virus. A 3D invasiveness assay is predictive for tumor reduction in vivo. Chondramid B, epothilone B, and pretubulysin D diminish KS-like lesions in vivo.
    • Observations on Texas hypoxylons, including two new Hypoxylon species and widespread environmental isolates of the H. croceum complex identified by a polyphasic approach

      Sir, Esteban B.; Becker, Kevin; Lambert, Christopher; Bills, Gerald F.; Kuhnert, Eric; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Taylor & Francis, 2019-01-01)
    • Diversity of Tilletiopsis-Like Fungi in Exobasidiomycetes (Ustilaginomycotina) and Description of Six Novel Species.

      Richter, Christian; Yurkov, Andrey M; Boekhout, Teun; Stadler, Marc; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Frontiers, 2019-01-01)
      In 2006 several yeast-like fungi were isolated from apples that showed a postharvest disorder named "white haze." These strains were morphologically and molecularly assigned to the genus Tilletiopsis. Following the recent reclassification of yeasts in Ustilaginomycotina and the genus Tilletiopsis in particular, species that caused "white haze" disorder were re-identified based on the phylogenetic analysis of five DNA-loci (ITS, LSU, SSU, RPB2, and TEF1) and analysis of D1/D2 domains of the 26S/28S rRNA (LSU). Six novel species belonging to three orders in the Exobasidiomycetes, namely Entyloma belangeri (holotype: CBS 111600; ex-type: DSM 29114) MB 823155, Entyloma davenportii (holotype: CBS 111604; ex-type: DSM 100135) MB 823154, Entyloma elstari (holotype: CBS 111593; ex-type: DSM 29113) MB 823153, Entyloma randwijkense (holotype: CBS 111606; ex-type: DSM 100136) MB 823156, Jamesdicksonia mali (holotype: CBS 111625; ex-type: DSM 29121) MB 823151 and Golubevia heteromorpha (holotype: CBS 111610; ex-type: DSM 100176) MB 823152 are proposed to accommodate these strains. In addition, sequences representing phylogenetically related but yet undescribed fungi were obtained from GenBank in order to show the diversity of Tilletiopsis-like yeast states in Exobasidiomycetes.