Now showing items 1-20 of 3498

    • Virus Irradiation and COVID-19 Disease

      Durante, Marco; Schulze, Kai; Incerti, Sebastien; Francis, Ziad; Zein, Sara; Guzmán, Carlos Alberto; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Frontiers, 2020-10-20)
      Virus irradiation has been performed for many decades for basic research studies, sterilization, and vaccine development. The COVID-19 outbreak is currently causing an enormous effort worldwide for finding a vaccine against coronavirus. High doses of γ-rays can be used for the development of vaccines that exploit inactivated virus. This technique has been gradually replaced by more practical methods, in particular the use of chemicals, but irradiation remains a simple and effective method used in some cases. The technique employed for inactivating a virus has an impact on its ability to induce an adaptive immune response able to confer effective protection. We propose here that accelerated heavy ions can be used to inactivate SARS-CoV-2 viruses with small damage to the spike proteins of the envelope and can then provide an intact virion for vaccine development.
    • Synthesis and Biopharmaceutical Characterization of Amphiphilic Squalenyl Derivative Based Versatile Drug Delivery Platform.

      Ho, Duy-Khiet; Christmann, Rebekka; Murgia, Xabier; de Rossi, Chiara; Frisch, Sarah; Koch, Marcus; Schaefer, Ulrich F; Loretz, Brigitta; Desmaele, Didier; Couvreur, Patrick; et al. (Frontiers, 2020-10-19)
      Hepatitis C virus (HCV) has no animal reservoir, infecting only humans. To investigate species barrier determinants limiting infection of rodents, murine liver complementary DNA library screening was performed, identifying transmembrane proteins Cd302 and Cr1l as potent restrictors of HCV propagation. Combined ectopic expression in human hepatoma cells impeded HCV uptake and cooperatively mediated transcriptional dysregulation of a noncanonical program of immunity genes. Murine hepatocyte expression of both factors was constitutive and not interferon inducible, while differences in liver expression and the ability to restrict HCV were observed between the murine orthologs and their human counterparts. Genetic ablation of endogenous Cd302 expression in human HCV entry factor transgenic mice increased hepatocyte permissiveness for an adapted HCV strain and dysregulated expression of metabolic process and host defense genes. These findings highlight human-mouse differences in liver-intrinsic antiviral immunity and facilitate the development of next-generation murine models for preclinical testing of HCV vaccine candidates.
    • Unambiguous identification of fungi: where do we stand and how accurate and precise is fungal DNA barcoding?

      Lücking, Robert; Aime, M Catherine; Robbertse, Barbara; Miller, Andrew N; Ariyawansa, Hiran A; Aoki, Takayuki; Cardinali, Gianluigi; Crous, Pedro W; Druzhinina, Irina S; Geiser, David M; et al. (BMC, 2020-07-10)
      True fungi (Fungi) and fungus-like organisms (e.g. Mycetozoa, Oomycota) constitute the second largest group of organisms based on global richness estimates, with around 3 million predicted species. Compared to plants and animals, fungi have simple body plans with often morphologically and ecologically obscure structures. This poses challenges for accurate and precise identifications. Here we provide a conceptual framework for the identification of fungi, encouraging the approach of integrative (polyphasic) taxonomy for species delimitation, i.e. the combination of genealogy (phylogeny), phenotype (including autecology), and reproductive biology (when feasible). This allows objective evaluation of diagnostic characters, either phenotypic or molecular or both. Verification of identifications is crucial but often neglected. Because of clade-specific evolutionary histories, there is currently no single tool for the identification of fungi, although DNA barcoding using the internal transcribed spacer (ITS) remains a first diagnosis, particularly in metabarcoding studies. Secondary DNA barcodes are increasingly implemented for groups where ITS does not provide sufficient precision. Issues of pairwise sequence similarity-based identifications and OTU clustering are discussed, and multiple sequence alignment-based phylogenetic approaches with subsequent verification are recommended as more accurate alternatives. In metabarcoding approaches, the trade-off between speed and accuracy and precision of molecular identifications must be carefully considered. Intragenomic variation of the ITS and other barcoding markers should be properly documented, as phylotype diversity is not necessarily a proxy of species richness. Important strategies to improve molecular identification of fungi are: (1) broadly document intraspecific and intragenomic variation of barcoding markers; (2) substantially expand sequence repositories, focusing on undersampled clades and missing taxa; (3) improve curation of sequence labels in primary repositories and substantially increase the number of sequences based on verified material; (4) link sequence data to digital information of voucher specimens including imagery. In parallel, technological improvements to genome sequencing offer promising alternatives to DNA barcoding in the future. Despite the prevalence of DNA-based fungal taxonomy, phenotype-based approaches remain an important strategy to catalog the global diversity of fungi and establish initial species hypotheses.
    • Simplicilones A and B Isolated from the Endophytic Fungus SPC3.

      Anoumedem, Elodie Gisèle M; Mountessou, Bel Youssouf G; Kouam, Simeon F; Narmani, Abolfazl; Surup, Frank; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MDPI, 2020-10-29)
      Two new tetracyclic polyketides with a spirocenter, simplicilones A (1) and B (2) were isolated from the broth-culture of the endophytic fungus Simplicilliumsubtropicum (SPC3) in the course of our screening for new bioactive secondary metabolites. This endophytoic fungus is naturally harboured in the fresh bark of the Cameroonian medicinal plant Duguetia staudtii (Engl. and Diels) Chatrou. The planar structures of the simplicilones were elucidated by MS and 1D as well as 2D NMR spectroscopic techniques. The relative configuration was assigned by NOESY experiments in conjunction with coupling constants; subsequently, the absolute configurations were assigned by the modified Mosher's method. The compounds showed weak cytotoxic effects against the cell line KB3.1 (in vitro cytotoxicity (IC50) = 25 µg/mL for 1, 29 µg/mL for 2), but were inactive against the tested Gram-positive and Gram-negative bacteria as well as fungi.
    • Directing Drugs to Bugs: Antibiotic-Carbohydrate Conjugates Targeting Biofilm-Associated Lectins of Pseudomonas aeruginosa .

      Meiers, Joscha; Zahorska, Eva; Röhrig, Teresa; Hauck, Dirk; Wagner, Stefanie; Titz, Alexander; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (ACS, 2020-10-02)
      Chronic infections by Pseudomonas aeruginosa are characterized by biofilm formation, which effectively enhances resistance toward antibiotics. Biofilm-specific antibiotic delivery could locally increase drug concentration to break antimicrobial resistance and reduce the drug's peripheral side effects. Two extracellular P. aeruginosa lectins, LecA and LecB, are essential structural components for biofilm formation and thus render a possible anchor for biofilm-targeted drug delivery. The standard-of-care drug ciprofloxacin suffers from severe systemic side effects and was therefore chosen for this approach. We synthesized several ciprofloxacin-carbohydrate conjugates and established a structure-activity relationship. Conjugation of ciprofloxacin to lectin probes enabled biofilm accumulation in vitro, reduced the antibiotic's cytotoxicity, but also reduced its antibiotic activity against planktonic cells due to a reduced cell permeability and on target activity. This work defines the starting point for new biofilm/lectin-targeted drugs to modulate antibiotic properties and ultimately break antimicrobial resistance.
    • A publicly accessible database for genome sequences supports tracing of transmission chains and epidemics.

      Frentrup, Martinique; Zhou, Zhemin; Steglich, Matthias; Meier-Kolthoff, Jan P; Göker, Markus; Riedel, Thomas; Bunk, Boyke; Spröer, Cathrin; Overmann, Jörg; Blaschitz, Marion; et al. (Microbiology Society, 2020-07-29)
      Clostridioides difficile is the primary infectious cause of antibiotic-associated diarrhea. Local transmissions and international outbreaks of this pathogen have been previously elucidated by bacterial whole-genome sequencing, but comparative genomic analyses at the global scale were hampered by the lack of specific bioinformatic tools. Here we introduce a publicly accessible database within EnteroBase ( that automatically retrieves and assembles C. difficile short-reads from the public domain, and calls alleles for core-genome multilocus sequence typing (cgMLST). We demonstrate that comparable levels of resolution and precision are attained by EnteroBase cgMLST and single-nucleotide polymorphism analysis. EnteroBase currently contains 18 254 quality-controlled C. difficile genomes, which have been assigned to hierarchical sets of single-linkage clusters by cgMLST distances. This hierarchical clustering is used to identify and name populations of C. difficile at all epidemiological levels, from recent transmission chains through to epidemic and endemic strains. Moreover, it puts newly collected isolates into phylogenetic and epidemiological context by identifying related strains among all previously published genome data. For example, HC2 clusters (i.e. chains of genomes with pairwise distances of up to two cgMLST alleles) were statistically associated with specific hospitals (P<10-4) or single wards (P=0.01) within hospitals, indicating they represented local transmission clusters. We also detected several HC2 clusters spanning more than one hospital that by retrospective epidemiological analysis were confirmed to be associated with inter-hospital patient transfers. In contrast, clustering at level HC150 correlated with k-mer-based classification and was largely compatible with PCR ribotyping, thus enabling comparisons to earlier surveillance data. EnteroBase enables contextual interpretation of a growing collection of assembled, quality-controlled C. difficile genome sequences and their associated metadata. Hierarchical clustering rapidly identifies database entries that are related at multiple levels of genetic distance, facilitating communication among researchers, clinicians and public-health officials who are combatting disease caused by C. difficile.
    • WAVE1 and WAVE2 have distinct and overlapping roles in controlling actin assembly at the leading edge.

      Tang, Qing; Schaks, Matthias; Koundinya, Neha; Yang, Changsong; Pollard, Luther W; Svitkina, Tatyana M; Rottner, Klemens; Goode, Bruce L; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (American Society for Cell Biology, 2020-07-22)
      SCAR/WAVE proteins and Arp2/3 complex assemble branched actin networks at the leading edge. Two isoforms of SCAR/WAVE, WAVE1 and WAVE2, reside at the leading edge, yet it has remained unclear whether they perform similar or distinct roles. Further, there have been conflicting reports about the Arp2/3-independent biochemical activities of WAVE1 on actin filament elongation. To investigate this in vivo, we knocked out WAVE1 and WAVE2 genes, individually and together, in B16-F1 melanoma cells. We demonstrate that WAVE1 and WAVE2 are redundant for lamellipodia formation and motility. However, there is a significant decrease in the rate of leading edge actin extension in WAVE2 KO cells, and an increase in WAVE1 KO cells. The faster rates of actin extension in WAVE1 KO cells are offset by faster retrograde flow, and therefore do not translate into faster lamellipodium protrusion. Thus, WAVE1 restricts the rate of actin extension at the leading edge, and appears to couple actin networks to the membrane to drive protrusion. Overall, these results suggest that WAVE1 and WAVE2 have redundant roles in promoting Arp2/3-dependent actin nucleation and lamellipodia formation, but distinct roles in controlling actin network extension and harnessing network growth to cell protrusion.
    • Growth-uncoupled isoprenoid synthesis in Rhodobacter sphaeroides.

      Orsi, Enrico; Mougiakos, Ioannis; Post, Wilbert; Beekwilder, Jules; Dompè, Marco; Eggink, Gerrit; van der Oost, John; Kengen, Servé W M; Weusthuis, Ruud A; HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany. (BMC, 2020-07-13)
      Microbial cell factories are usually engineered and employed for cultivations that combine product synthesis with growth. Such a strategy inevitably invests part of the substrate pool towards the generation of biomass and cellular maintenance. Hence, engineering strains for the formation of a specific product under non-growth conditions would allow to reach higher product yields. In this respect, isoprenoid biosynthesis represents an extensively studied example of growth-coupled synthesis with rather unexplored potential for growth-independent production. Rhodobacter sphaeroides is a model bacterium for isoprenoid biosynthesis, either via the native 2-methyl-d-erythritol 4-phosphate (MEP) pathway or the heterologous mevalonate (MVA) pathway, and for poly-β-hydroxybutyrate (PHB) biosynthesis.
    • CYP154C5 Regioselectivity in Steroid Hydroxylation Explored by Substrate Modifications and Protein Engineering.

      Bracco, Paula; Wijma, Hein J; Nicolai, Bastian; Rodriguez Buitrago, Jhon Alexander; Klünemann, Thomas; Vila, Agustina; Schrepfer, Patrick; Blankenfeldt, Wulf; Janssen, Dick B; Schallmey, Anett; et al. (Wiley, 2020-11-04)
      CYP154C5 from Nocardia farcinica is a P450 monooxygenase able to hydroxylate a range of steroids with high regio- and stereoselectivity at the 16a-position. Using protein engineering and substrate modifications based on the crystal structure of CYP154C5, an altered regioselectivity of the enzyme in steroid hydroxylation had been achieved. Thus, conversion of progesterone by mutant CYP154C5 F92A resulted in formation of the corresponding 21-hydroxylated product 11-deoxycorticosterone in addition to 16α-hydroxylation. Using MD simulation, this altered regioselectivity appeared to result from an alternate binding mode of the steroid in the active site of mutant F92A. MD simulation further suggested that water entrance to the active site caused higher uncoupling in this mutant. Moreover, exclusive 15α-hydroxylation was observed for wild-type CYP154C5 in the conversion of 5a-androstan-3-one, lacking an oxy-functional group at C17. Overall, our data give valuable insight into the structure-function relationship of this cytochrome P450 monooxygenase for steroid hydroxylation.
    • Editorial EJPB - Biobarriers 2018.

      Fuhrmann, Gregor; Loretz, Brigitta; Schneider-Daum, Nicole; Lehr, Claus-Michael; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Elsevier, 2020-11-02)
      [No abstract available]
    • An ambruticin-sensing complex modulates Myxococcus xanthus development and mediates myxobacterial interspecies communication.

      Marcos-Torres, Francisco Javier; Volz, Carsten; Müller, Rolf; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Nature Pulishing Group, 2020-11-04)
      Starvation induces cell aggregation in the soil bacterium Myxococcus xanthus, followed by formation of fruiting bodies packed with myxospores. Sporulation in the absence of fruiting bodies can be artificially induced by high concentrations of glycerol through unclear mechanisms. Here, we show that a compound (ambruticin VS-3) produced by a different myxobacterium, Sorangium cellulosum, affects the development of M. xanthus in a similar manner. Both glycerol (at millimolar levels) and ambruticin VS-3 (at nanomolar concentrations) inhibit M. xanthus fruiting body formation under starvation, and induce sporulation in the presence of nutrients. The response is mediated in M. xanthus by three hybrid histidine kinases (AskA, AskB, AskC) that form complexes interacting with two major developmental regulators (MrpC, FruA). In addition, AskB binds directly to the mrpC promoter in vitro. Thus, our work indicates that the AskABC-dependent regulatory pathway mediates the responses to ambruticin VS-3 and glycerol. We hypothesize that production of ambruticin VS-3 may allow S. sorangium to outcompete M. xanthus under both starvation and growth conditions in soil.
    • An Adaptive Control Scheme for Interleukin-2 Therapy.

      Khailaie, Sahamoddin; Montaseri, Ghazal; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier (Cell Press), 2020-10-12)
      Regulatory T cells (Treg) are suppressor cells that control self-reactive and excessive effector conventional T helper cell (Tconv) responses. Breakdown of the balance between Tregs and Tconvs is a hallmark of autoimmune and inflammatory diseases. Interleukin-2 (IL-2) is a growth factor for both populations and subtle leverage to restore the healthy immune balance in IL-2 therapy. By using a mechanistic mathematical model, we introduced an adaptive control strategy to design the minimal therapeutic IL-2 dosage required to increase and stabilize Treg population and restrict inflammatory response. This adaptive protocol allows for dose adjustments based on the feedback of the immune kinetics of the patient. Our simulation results showed that a minimal Treg population was required to restrict the transient side effect of IL-2 injections on the effector Tconv response. In silico results suggested that a combination of IL-2 and adoptive Treg transfer therapies can limit this side effect.
    • Solving the nonlinear boundary layer flow equations with pressure gradient and radiation

      Xenos, Michalis A.; Petropoulou, Eugenia N.; Siokis, Anastasios; Mahabaleshwar, U. S.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (MDPI, 2020-05-01)
      The physical problem under consideration is the boundary layer problem of an incompressible, laminar flow, taking place over a flat plate in the presence of a pressure gradient and radiation. For the mathematical formulation of the problem, the partial differential equations of continuity, energy, and momentum are taken into consideration with the boundary layer simplifications. Using the dimensionless Falkner–Skan transformation, a nonlinear, nonhomogeneous, coupled system of partial differential equations (PDEs) is obtained, which is solved via the homotopy analysis method. The obtained analytical solution describes radiation and pressure gradient effects on the boundary layer flow. These analytical results reveal that the adverse or favorable pressure gradient influences the dimensionless velocity and the dimensionless temperature of the boundary layer. An adverse pressure gradient causes significant changes on the dimensionless wall shear parameter and the dimensionless wall heat-transfer parameter. Thermal radiation influences the thermal boundary layer. The analytical results are in very good agreement with the corresponding numerical ones obtained using a modification of the Keller’s-box method.
    • Terricaulis silvestris gen. Nov., sp. nov., a novel prosthecate, budding member of the family caulobacteraceae isolated from forest soil

      Vieira, Selma; Pascual, Javier; Boedeker, Christian; Geppert, Alicia; Riedel, Thomas; Rohde, Manfred; Overmann, Jörg; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Microbiology Society, 2020-08-07)
      The family Caulobacteraceae comprises prosthecate bacteria with a dimorphic cell cycle and also non-prosthecate bacteria. Cells of all described species divide by binary fission. Strain 0127_4T was isolated from forest soil in Baden Württemberg (Germany) and determined to be the first representative of the family Caulobacteraceae which divided by budding. Cells of strain 0127_4T were Gram-negative, rod-shaped, prosthecate, motile by means of a polar flagellum, non-spore-forming and non-capsulated. The strain formed small white colonies and grew aerobically and chemo-organotrophically utilizing organic acids, amino acids and proteinaceous substrates. 16S rRNA gene sequence analysis indicated that this bacterium was related to Aquidulcibacter paucihalophilus TH1-2T and Asprobacter aquaticus DRW22-8T with 91.3 and 89.7% sequence similarity, respectively. Four unidentified glycolipids were detected as the major polar lipids and, unlike all described members of the family Caulobacteraceae, phosphatidylglycerol was absent. The major fatty acids were summed feature 8 (C18 : 1ω7c/C18 : 1ω6c), summed feature 9 (iso-C17 : 1ω9c/C16 : 0 10-methyl), C16 : 0 and summed feature 3 (C16 : 1ω6c/C16 : 1ω7c). The major respiratory quinone was Q-10. The G+C content of the genomic DNA was 63.5 %. Based on the present taxonomic characterization, strain 0127_4T represents a novel species of a new genus, Terricaulis silvestris gen. nov., sp. nov. The type strain of Terricaulis silvestris is 0127_4T (=DSM 104635T=CECT 9243T).
    • Dissecting Herpes Simplex Virus 1-Induced Host Shutoff at the RNA Level.

      Friedel, Caroline C; Whisnant, Adam W; Djakovic, Lara; Rutkowski, Andrzej J; Friedl, Marie-Sophie; Kluge, Michael; Williamson, James C; Sai, Somesh; Vidal, Ramon Oliveira; Sauer, Sascha; et al. (American Society for Microbilogy (ASM), 2020-11-04)
      Herpes simplex virus 1 (HSV-1) induces a profound host shut-off during lytic infection. The virion host shut-off (vhs) protein plays a key role in this process by efficiently cleaving host and viral mRNAs. Furthermore, the onset of viral DNA replication is accompanied by a rapid decline in host transcriptional activity. To dissect relative contributions of both mechanisms and elucidate gene-specific host transcriptional responses throughout the first 8h of lytic HSV-1 infection, we employed RNA-seq of total, newly transcribed (4sU-labelled) and chromatin-associated RNA in wild-type (WT) and Δvhs infection of primary human fibroblasts. Following virus entry, vhs activity rapidly plateaued at an elimination rate of around 30% of cellular mRNAs per hour until 8h p.i. In parallel, host transcriptional activity dropped to 10-20%. While the combined effects of both phenomena dominated infection-induced changes in total RNA, extensive gene-specific transcriptional regulation was observable in chromatin-associated RNA and was surprisingly concordant between WT and Δvhs infection. Both induced strong transcriptional up-regulation of a small subset of genes that were poorly expressed prior to infection but already primed by H3K4me3 histone marks at their promoters. Most interestingly, analysis of chromatin-associated RNA revealed vhs-nuclease-activity-dependent transcriptional down-regulation of at least 150 cellular genes, in particular of many integrin adhesome and extracellular matrix components. This was accompanied by a vhs-dependent reduction in protein levels by 8h p.i. for many of these genes. In summary, our study provides a comprehensive picture of the molecular mechanisms that govern cellular RNA metabolism during the first 8h of lytic HSV-1 infection.IMPORTANCE The HSV-1 virion host shut-off (vhs) protein efficiently cleaves both host and viral mRNAs in a translation-dependent manner. In this study, we model and quantify changes in vhs activity as well as virus-induced global loss of host transcriptional activity during productive HSV-1 infection. In general, HSV-1-induced alterations in total RNA levels were dominated by these two global effects. In contrast, chromatin-associated RNA depicted gene-specific transcriptional changes. This revealed highly concordant transcriptional changes in WT and Δvhs infection, confirmed DUX4 as a key transcriptional regulator in HSV-1 infection and depicted vhs-dependent, transcriptional down-regulation of the integrin adhesome and extracellular matrix components. The latter explained seemingly gene-specific effects previously attributed to vhs-mediated mRNA degradation and resulted in a concordant loss in protein levels by 8h p.i. for many of the respective genes.
    • Computational strategies to combat COVID-19: useful tools to accelerate SARS-CoV-2 and coronavirus research.

      Hufsky, Franziska; Lamkiewicz, Kevin; Almeida, Alexandre; Aouacheria, Abdel; Arighi, Cecilia; Bateman, Alex; Baumbach, Jan; Beerenwinkel, Niko; Brandt, Christian; Cacciabue, Marco; et al. (Oxford Academic, 2020-11-04)
      SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel virus of the family Coronaviridae. The virus causes the infectious disease COVID-19. The biology of coronaviruses has been studied for many years. However, bioinformatics tools designed explicitly for SARS-CoV-2 have only recently been developed as a rapid reaction to the need for fast detection, understanding and treatment of COVID-19. To control the ongoing COVID-19 pandemic, it is of utmost importance to get insight into the evolution and pathogenesis of the virus. In this review, we cover bioinformatics workflows and tools for the routine detection of SARS-CoV-2 infection, the reliable analysis of sequencing data, the tracking of the COVID-19 pandemic and evaluation of containment measures, the study of coronavirus evolution, the discovery of potential drug targets and development of therapeutic strategies. For each tool, we briefly describe its use case and how it advances research specifically for SARS-CoV-2. All tools are free to use and available online, either through web applications or public code repositories.
    • Eosinophilic pulmonary vasculitis as a manifestation of the hyperinflammatory phase of COVID-19.

      Luecke, Eva; Jeron, Andreas; Kroeger, Andrea; Bruder, Dunja; Stegemann-Koniszewski, Sabine; Jechorek, Doerthe; Borucki, Katrin; Reinhold, Dirk; Reinhold, Annegret; Foellner, Sebastian; et al. (Elsevier, 2020-10-26)
      No abstract available
    • Synthetic rewiring and boosting type I interferon responses for visualization and counteracting viral infections.

      Gödecke, Natascha; Riedel, Jan; Herrmann, Sabrina; Behme, Sara; Rand, Ulfert; Kubsch, Tobias; Cicin-Sain, Luka; Hauser, Hansjörg; Köster, Mario; Wirth, Dagmar; et al. (Oxford Academic, 2020-11-18)
      Mammalian first line of defense against viruses is accomplished by the interferon (IFN) system. Viruses have evolved numerous mechanisms to reduce the IFN action allowing them to invade the host and/or to establish latency. We generated an IFN responsive intracellular hub by integrating the synthetic transactivator tTA into the chromosomal Mx2 locus for IFN-based activation of tTA dependent expression modules. The additional implementation of a synthetic amplifier module with positive feedback even allowed for monitoring and reacting to infections of viruses that can antagonize the IFN system. Low and transient IFN amounts are sufficient to trigger these amplifier cells. This gives rise to higher and sustained-but optionally de-activatable-expression even when the initial stimulus has faded out. Amplification of the IFN response induced by IFN suppressing viruses is sufficient to protect cells from infection. Together, this interfaced sensor/actuator system provides a toolbox for robust sensing and counteracting viral infections.
    • Unsaturated Fatty Acids Control Biofilm Formation of and Other Gram-Positive Bacteria.

      Yuyama, Kamila Tomoko; Rohde, Manfred; Molinari, Gabriella; Stadler, Marc; Abraham, Wolf-Rainer; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MDPI, 2020-11-08)
      Infections involving biofilms are difficult to treat due to increased resistances against antibiotics and the immune system. Hence, there is an urgent demand for novel drugs against biofilm infections. During our search for novel biofilm inhibitors from fungi, we isolated linoleic acid from the ascomycete Hypoxylon fragiforme which showed biofilm inhibition of several bacteria at sub-MIC concentrations. Many fatty acids possess antimicrobial activities, but their minimum inhibitory concentrations (MIC) are high and reports on biofilm interferences are scarce. We demonstrated that not only linoleic acid but several unsaturated long-chain fatty acids inhibited biofilms at sub-MIC concentrations. The antibiofilm activity exerted by long-chain fatty acids was mainly against Gram-positive bacteria, especially against Staphylococcus aureus. Micrographs of treated S. aureus biofilms revealed a reduction in the extracellular polymeric substances, pointing to a possible mode of action of fatty acids on S. aureus biofilms. The fatty acids had a strong species specificity. Poly-unsaturated fatty acids had higher activities than saturated ones, but no obvious rule could be found for the optimal length and desaturation for maximal activity. As free fatty acids are non-toxic and ubiquitous in food, they may offer a novel tool, especially in combination with antibiotics, for the control of biofilm infections.
    • Buchwald-Hartwig versus Microwave-Assisted Amination of Chloroquinolines: En Route to the Pyoverdin Chromophore

      Seubert, Philipp; Freund, Marcel; Rudolf, Richard; Lin, Yulin; Altevogt, Luca; Bilitewski, Ursula; Baro, Angelika; Laschat, Sabine; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Thieme Verlag, 2020-07-22)
      The reaction of 2-chloro-3-nitroquinoline and a series of amines and aminoalkanoates under basic microwave-mediated conditions and Buchwald-Hartwig amination conditions is reported. The microwave irradiation favored the reaction with amines, resulting in yields up to 80%, while amino acid functionalization gave yields comparable to those of BuchwaldHartwig amination. (2R)-4-[(6,7-dimethoxy-3-nitroquinolinyl)amino]-2-hydroxybutanoate could be successfully cyclized to the pyoverdin chromophore, a subunit of siderophores.