• Six Heterocyclic Metabolites from the Myxobacterium Labilithrix luteola.

      Mulwa, Lucky S; Jansen, Rolf; Praditya, Dimas F; Mohr, Kathrin I; Wink, Joachim; Steinmann, Eike; Stadler, Marc; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-02-28)
      Two new secondary metabolites, labindole A [2-methyl-3-(2-nitroethyl)-3H-indole] (1) and labindole B [2-methyl-3-(2-nitrovinyl)-3H-indole] (2), were isolated from the myxobacteriumLabilithrixluteola(DSM 27648T). Additionally, four metabolites3,4,5and6already known from other sources were obtained. Their structures were elucidated from high resolution electrospray ionisation mass spectrometry (HRESIMS) and 1D and 2D nuclear magnetic resonance (NMR) spectroscopy data and their relative configuration was assigned based on nuclear Overhauser effect (NOE) and vicinal ¹H-NMR coupling data. The compounds where tested for biological activities; labindoles A (1) and B (2) exhibited significant activity against Hepatitis C Virus, 9H-carbazole (3), 3-chloro-9H-carbazole (4) and 4-hydroxymethyl-quinoline (5) showed antifungal activities. Moreover, compound3had weak to moderate antibacterial activities, while labindoles A (1) and B (2) were devoid of significant antifungal and antibacterial effects.
    • Successful retreatment of a patient with chronic hepatitis C genotype 2k/1b virus with ombitasvir/paritaprevir/ritonavir plus dasabuvir.

      Todt, Daniel; Schlevogt, Bernhard; Deterding, Katja; Grundhoff, Adam; Manns, Michael P; Wedemeyer, Heiner; Fischer, Nicole; Cornberg, Markus; Steinmann, Eike; Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany. (2017-01-18)
    • Susceptibility of Chikungunya Virus to Inactivation by Heat and Commercially and World Health Organization-Recommended Biocides.

      Franz, Sergej; Friesland, Martina; Passos, Vânia; Todt, Daniel; Simmons, Graham; Goffinet, Christine; Steinmann, Eike; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany. (Oxford University Press, 2018-09-22)
      Despite increasing clinical relevance of Chikungunya virus (CHIKV) infection, caused by a rapidly emerging pathogen, recommended guidelines for its inactivation do not exist. In this study, we investigated the susceptibility of CHIKV to inactivation by heat and commercially available hand, surface, and World Health Organization-recommended disinfectants to define CHIKV prevention protocols for healthcare systems.
    • Tracking HCV protease population diversity during transmission and susceptibility of founder populations to antiviral therapy.

      Khera, Tanvi; Todt, Daniel; Vercauteren, Koen; McClure, C Patrick; Verhoye, Lieven; Farhoudi, Ali; Bhuju, Sabin; Geffers, Robert; Baumert, Thomas F; Steinmann, Eike; et al. (2017-03)
      Due to the highly restricted species-tropism of Hepatitis C virus (HCV) a limited number of animal models exist for pre-clinical evaluation of vaccines and antiviral compounds. The human-liver chimeric mouse model allows heterologous challenge with clinically relevant strains derived from patients. However, to date, the transmission and longitudinal evolution of founder viral populations in this model have not been characterized in-depth using state-of-the-art sequencing technologies. Focusing on NS3 protease encoding region of the viral genome, mutant spectra in a donor inoculum and individual recipient mice were determined via Illumina sequencing and compared, to determine the effects of transmission on founder viral population complexity. In all transmissions, a genetic bottleneck was observed, although diverse viral populations were transmitted in each case. A low frequency cloud of mutations (<1%) was detectable in the donor inoculum and recipient mice, with single nucleotide variants (SNVs) > 1% restricted to a subset of nucleotides. The population of SNVs >1% was reduced upon transmission while the low frequency SNV cloud remained stable. Fixation of multiple identical synonymous substitutions was apparent in independent transmissions, and no evidence for reversion of T-cell epitopes was observed. In addition, susceptibility of founder populations to antiviral therapy was assessed. Animals were treated with protease inhibitor (PI) monotherapy to track resistance associated substitution (RAS) emergence. Longitudinal analyses revealed a decline in population diversity under therapy, with no detectable RAS >1% prior to therapy commencement. Despite inoculation from a common source and identical therapeutic regimens, unique RAS emergence profiles were identified in different hosts prior to and during therapeutic failure, with complex mutational signatures at protease residues 155, 156 and 168 detected. Together these analyses track viral population complexity at high-resolution in the human-liver chimeric mouse model post-transmission and under therapeutic intervention, revealing novel insights into the evolutionary processes which shape viral protease population composition at various critical stages of the viral life-cycle.
    • Two New Cyathane Diterpenoids from Mycelial Cultures of the Medicinal Mushroom Hericium erinaceus and the Rare Species, Hericium flagellum.

      Rupcic, Zeljka; Rascher, Monique; Kanaki, Sae; Köster, Reinhard W; Stadler, Marc; Wittstein, Kathrin; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-03-06)
      Basidiomycetes of the genusHericiumare among the most praised medicinal and edible mushrooms, which are known to produce secondary metabolites with the potential to treat neurodegenerative diseases. This activity has been attributed to the discovery of various terpenoids that can stimulate the production of nerve growth factor (NGF) or (as established more recently) brain-derived neurotrophic factor (BDNF) in cell-based bioassays. The present study reports on the metabolite profiles of a Lion's Mane mushroom (Hericium erinaceus) strain and a strain of the rare species,Hericium flagellum(synonymH. alpestre). While we observed highly similar metabolite profiles between the two strains that were examined, we isolated two previously undescribed metabolites, given the trivial names erinacines Z1 and Z2. Their chemical structures were elucidated by means of nuclear magnetic resonance (NMR) spectroscopy and high resolution mass spectrometry. Along with six further, previously identified cyathane diterpenes, the novel erinacines were tested for neurotrophin inducing effects. We found that erinacines act onBDNF, which is a neurotrophic factor that has been reported recently by us to be induced by the corallocins, but as well onNGFexpression, which is consistent with the literature.
    • Virucidal Activity of World Health Organization-Recommended Formulations Against Enveloped Viruses, Including Zika, Ebola, and Emerging Coronaviruses.

      Siddharta, Anindya; Pfaender, Stephanie; Vielle, Nathalie Jane; Dijkman, Ronald; Friesland, Martina; Becker, Britta; Yang, Jaewon; Engelmann, Michael; Todt, Daniel; Windisch, Marc P; et al. (2017-03-15)
      The World Health Organization (WHO) published 2 alcohol-based formulations to be used in healthcare settings and for outbreak-associated infections, but inactivation efficacies of these products have not been determined against (re-)emerging viruses. In this study, we evaluated the virucidal activity of these WHO products in a comparative analysis. Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) as (re-)emerging viral pathogens and other enveloped viruses could be efficiently inactivated by both WHO formulations, implicating their use in healthcare systems and viral outbreak situations.
    • Virucidal efficacy of a sonicated hydrogen peroxide system (trophon EPR) following European and German test methods.

      Becker, Britta; Bischoff, Birte; Brill, Florian H H; Steinmann, Eike; Steinmann, Jochen; TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany. (2017-01-01)
      The virucidal efficacy of an automated ultrasound probe disinfector (trophon® EPR) was evaluated in a three step procedure according to European and German test methods. This system uses sonicated hydrogen peroxide mist (35%) at elevated temperature (50°C) in a closed chamber with control of all parameters within a 7 minute cycle. Methods: In the first step of examination, the peroxide solution was tested in a quantitative suspension assay according to the Guideline of Deutsche Vereinigung zur Bekämpfung der Viruskrankheiten (DVV) e.V. and Robert Koch-Institute (RKI) and in parallel with the European Norm EN 14476 with all test viruses creating a virucidal claim. In the second step, the virucidal efficacy of the hydrogen peroxide solution was evaluated in a hard surface carrier test according to the Guideline of DVV with adenovirus, murine norovirus and parvovirus simulating practical conditions. Finally, the efficacy was evaluated by the automated system using stainless steel carriers inoculated with test virus and positioned at different levels inside the chamber.
    • Virucidal efficacy of peracetic acid for instrument disinfection.

      Becker, Britta; Brill, Florian H H; Todt, Daniel; Steinmann, Eike; Lenz, Johannes; Paulmann, Dajana; Bischoff, Birte; Steinmann, Jochen; TwinCore, Zentrum für experimentelle und klinische Infektionsforschng GmbH, Feodor-Lynen-Str.7, 30625 Hannover, Germany. (2017)
      Various peracetic-acid (PAA)-based products for processing flexible endoscopes on the market are often based on a two-component system including a cleaning step before the addition of PAA as disinfectant. The peracetic acid concentrations in these formulations from different manufacturers are ranging from 400 to 1500 ppm (part per million). These products are used at temperatures between 20 °C and 37 °C. Since information on the virus-inactivating properties of peracetic acid at different concentrations and temperature is missing, it was the aim of the study to evaluate peracetic acid solutions against test viruses using the quantitative suspension test, EN 14476. In addition, further studies were performed with the recently established European pre norm (prEN 17111:2017) describing a carrier assay for simulating practical conditions using frosted glass.