18 results on '"Carsten Volz"'
Search Results
2. Clinical Resistome Screening of 1,110 Escherichia coli Isolates Efficiently Recovers Diagnostically Relevant Antibiotic Resistance Biomarkers and Potential Novel Resistance Mechanisms
- Author
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Carsten Volz, Jonas Ramoni, Stephan Beisken, Valentina Galata, Andreas Keller, Achim Plum, Andreas E. Posch, and Rolf Müller
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functional metagenomics ,antibiotic resistance ,high-throughput screening ,biomarkers ,bioinformatics ,biostatistics ,Microbiology ,QR1-502 - Abstract
Multidrug-resistant pathogens represent one of the biggest global healthcare challenges. Molecular diagnostics can guide effective antibiotics therapy but relies on validated, predictive biomarkers. Here we present a novel, universally applicable workflow for rapid identification of antimicrobial resistance (AMR) biomarkers from clinical Escherichia coli isolates and quantitatively evaluate the potential to recover causal biomarkers for observed resistance phenotypes. For this, a metagenomic plasmid library from 1,110 clinical E. coli isolates was created and used for high-throughput screening to identify biomarker candidates against Tobramycin (TOB), Ciprofloxacin (CIP), and Trimethoprim-Sulfamethoxazole (TMP-SMX). Identified candidates were further validated in vitro and also evaluated in silico for their diagnostic performance based on matched genotype-phenotype data. AMR biomarkers recovered by the metagenomics screening approach mechanistically explained 77% of observed resistance phenotypes for Tobramycin, 76% for Trimethoprim-Sulfamethoxazole, and 20% Ciprofloxacin. Sensitivity for Ciprofloxacin resistance detection could be improved to 97% by complementing results with AMR biomarkers that are undiscoverable due to intrinsic limitations of the workflow. Additionally, when combined in a multiplex diagnostic in silico panel, the identified AMR biomarkers reached promising positive and negative predictive values of up to 97 and 99%, respectively. Finally, we demonstrate that the developed workflow can be used to identify potential novel resistance mechanisms.
- Published
- 2019
- Full Text
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3. miRMaster 2.0: multi-species non-coding RNA sequencing analyses at scale.
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Tobias Fehlmann, Fabian Kern, Omar Laham, Christina Backes, Jeffrey Solomon, Pascal Hirsch, Carsten Volz, Rolf Müller 0002, and Andreas Keller
- Published
- 2021
- Full Text
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4. Unusual peptide-binding proteins guide pyrroloindoline alkaloid formation in crocagin biosynthesis
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Sebastian Adam, Dazhong Zheng, Andreas Klein, Carsten Volz, William Mullen, Sally L. Shirran, Brian O. Smith, Olga V. Kalinina, Rolf Müller, Jesko Koehnke, University of St Andrews. Arctic Research Centre, University of St Andrews. School of Biology, University of St Andrews. Institute of Behavioural and Neural Sciences, and University of St Andrews. Biomedical Sciences Research Complex
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MCC ,General Chemical Engineering ,DAS ,QD ,General Chemistry ,QD Chemistry - Abstract
Funding: This work was supported by the European Research Council (Consolidator Grant 101002326 to J.K.). Ribosomally synthesized and post-translationally modified peptide natural products have provided many highly unusual scaffolds. This includes the intriguing alkaloids crocagins, which possess a tetracyclic core structure and whose biosynthesis has remained enigmatic. Here we use in vitro experiments to demonstrate that three proteins, CgnB, CgnC and CgnE, are sufficient for the production of the hallmark tetracyclic crocagin core from the precursor peptide CgnA. The crystal structures of the homologues CgnB and CgnE reveal them to be the founding members of a peptide-binding protein family and allow us to rationalize their distinct functions. We further show that the hydrolase CgnD liberates the crocagin core scaffold, which is subsequently N-methylated by CgnL. These insights allow us to propose a biosynthetic scheme for crocagins. Bioinformatic analyses based on these data led to the discovery of related biosynthetic pathways that may provide access to a structurally diverse family of peptide-derived pyrroloindoline alkaloids. Publisher PDF
- Published
- 2023
5. Expanding the Ajudazol Cytotoxin Scaffold: Insights from Genome Mining, Biosynthetic Investigations, and Novel Derivatives
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Hu Zeng, Joy Birkelbach, Judith Hoffmann, Alexander Popoff, Carsten Volz, and Rolf Müller
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Pharmacology ,Complementary and alternative medicine ,Cytotoxins ,Mutagenesis ,Multigene Family ,Organic Chemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Glycosyltransferases ,Myxococcales ,Genome, Bacterial ,Analytical Chemistry - Abstract
Myxobacteria have proven to be a rich source of natural products, but their biosynthetic potential seems to be underexplored given the high number of biosynthetic gene clusters present in their genomes. In this study, a truncated ajudazol biosynthetic gene cluster in
- Published
- 2022
6. Leben und Überleben im Boden
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Carsten Volz, Daniel Krug, and Rolf Müller
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Biology ,General Agricultural and Biological Sciences - Published
- 2020
7. Targeting the energy-coupling factor (ECF) transporters: identification of new tool compounds
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Eleonora Diamanti, Inda Setyawati, Spyridon Bousis, Paulo C. T. Souza, leticia mojas, lotteke Swier, Jörg Haupenthal, Paddy Gibson, carsten volz, weronika stanek, manuel Jaeger, jennifer herrmann, Siewert Marrink, jan-willem veening, rolf müller, dirk J. slotboom, and Anna K.H. Hirsch
- Abstract
The energy-coupling factor (ECF) transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. Their central role in the metabolism of bacteria and absence in humans make the ECF transporters a potential antibacterial target, which can be further investigated making use of a selective chemical probe. Here, we report on the virtual screening, design, synthesis, structure–activity relationships (SARs) and coarse-grained molecular dynamics simulations of the first class of inhibitors of the ECF transporters. We investigated the mechanism of action of this chemical class and profiled the best hit compounds regarding their pharmaceutical properties. The optimized hit has a minimum inhibitory concentration (MIC) value of 2 µg/mL against Streptococcus pneumoniae, which opens up the possibility to use this chemical class to investigate the role of the ECF transporters in health and disease.
- Published
- 2021
8. Discovery of Antibacterial Agents Inhibiting the Energy-Coupling Factor (ECF) Transporters by Structure-Based Virtual Screening
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manuel Jaeger, Anna K. H. Hirsch, Lotteke J Y M Swier, Paddy Gibson, Eleonora Diamanti, Carsten Volz, Inda Setyawati, Weronika K. Stanek, Jörg Haupenthal, Spyridon Bousis, Dirk Jan Slotboom, Jan-Willem Veening, leticia mojas, Jennifer Herrmann, and Rolf Müller
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Virtual screening ,biology ,Chemistry ,Transporter ,Metabolism ,biology.organism_classification ,Antimicrobial ,Transmembrane protein ,Mechanism of action ,Biochemistry ,medicine ,medicine.symptom ,Cytotoxicity ,Bacteria - Abstract
Here, we report on the virtual screening, design, synthesis and structure–activity relationships (SARs) of the first class of selective, antibacterial agents against the energy-coupling factor (ECF) transporters. The ECF transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. Because of their central role in the metabolism of bacteria and their absence in humans, ECF transporters are novel potential antimicrobial targets to tackle infection. The hit compound’s metabolic and plasma stability, the potency (20, MIC Streptococcus pneumoniae = 2 µg/mL), the absence of cytotoxicity and a lack of resistance development under the conditions tested here suggest that this scaffold may represent a promising starting point for the development of novel antimicrobial agents with an unprecedented mechanism of action.
- Published
- 2020
9. An Outer Membrane Vesicle‐Based Permeation Assay (OMPA) for Assessing Bacterial Bioavailability
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Bart-Jan Niebuur, Tobias Kraus, Adriely Goes, Anna-Lena Huber, Mohamed Ashraf M. Kamal, Marcus Koch, Gregor Fuhrmann, Robert Richter, Rolf Müller, Claus-Michael Lehr, Jean-Marie Pagès, Nicole Schneider-Daum, Carsten Volz, and Julia Vergalli
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Liposome ,Chemistry ,Vesicle ,Biomedical Engineering ,Phospholipid ,Biological Availability ,Porins ,Pharmaceutical Science ,Permeation ,Bioavailability ,Biomaterials ,chemistry.chemical_compound ,Membrane ,X-Ray Diffraction ,Gram-Negative Bacteria ,Scattering, Small Angle ,Biophysics ,Cell envelope ,Bacterial outer membrane - Abstract
When searching for new antibiotics against Gram-negative bacterial infections, a better understanding of the permeability across the cell envelope and tools to discriminate high from low bacterial bioavailability compounds are urgently needed. Inspired by the phospholipid vesicle-based permeation assay (PVPA), which was designed to predict non-facilitated permeation across phospholipid membranes, outer membrane vesicles (OMVs) of Escherichia coli either enriched or deficient of porins are employed to coat filter supports for predicting drug uptake across the complex cell envelope. OMVs and the obtained in vitro model are structurally and functionally characterized using cryo-TEM, SEM, CLSM, SAXS and light scattering techniques. In vitro permeability, obtained from our membrane model for a set of nine antibiotics, correlates with reported in bacterio accumulation data and allows to discriminate high from low accumulating antibiotics. In contrast, the correlation of the same data set generated by liposome-based comparator membranes is poor. This better correlation of the OMV-derived membranes points to the importance of hydrophilic membrane components, such as lipopolysaccharides and porins, since those features are lacking in liposomal comparator membranes. This approach can offer in future a high throughput screening tool with high predictive capacity or can help to identify compound- and bacteria-specific passive uptake pathways. This article is protected by copyright. All rights reserved.
- Published
- 2021
10. Chemische Struktur und Biosynthese der Crocagine, polycyclischer Peptide ribosomalen Ursprungs ausChondromyces crocatus
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Dirk Trauner, Carsten Volz, Jennifer Herrmann, Jesko Köhnke, Frank Surup, Sebastian Adam, Konrad Viehrig, Rolf Müller, and Antoine Abou Fayad
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010405 organic chemistry ,General Medicine ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences - Abstract
Sekundarmetabolom-Analysen in dem myxobakteriellen Naturstoffproduzenten Chondromyces crocatus Cm c5 fuhrten zur Isolierung und Charakterisierung der Crocagine, neuartiger polycyclischer Peptide mit Tetrahydropyrrolo[2,3-b]indol-Grundgerust. Der zugehorige Gencluster wurde durch eine Kombination aus gezielter Mutagenese und In-vitro-Experimenten zugeordnet. Auf Grundlage der Ergebnisse konnte ein Biosyntheseschema fur die Crocagine erstellt werden. Diese Naturstoffe werden aus den drei C-terminalen Aminosauren eines Vorlauferpeptides gebildet und gehoren daher zu einer neuen Klasse der ribosomal gebildeten und posttranslational modifizierten Peptide (RiPPs). Weiterhin konnte gezeigt werden, dass Crocagin A an das Regulatorprotein CsrA (“carbon storage regulator”) bindet, wodurch dessen Bindung an seine RNA-Wechselwirkungspartner unterdruckt wird.
- Published
- 2017
11. The AibR-isovaleryl coenzyme A regulator and its DNA binding site - a model for the regulation of alternative de novo isovaleryl coenzyme A biosynthesis in Myxococcus xanthus
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Wulf Blankenfeldt, Andrea Scrima, T. Bock, Vanessa Hering, Carsten Volz, Rolf Müller, and Hel,holtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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Models, Molecular ,0301 basic medicine ,Myxococcus xanthus ,Coenzyme A ,030106 microbiology ,Molecular Conformation ,03 medical and health sciences ,chemistry.chemical_compound ,Bacterial Proteins ,Structural Biology ,Transcription (biology) ,Operon ,Genetics ,Transcriptional regulation ,Binding site ,Promoter Regions, Genetic ,Binding Sites ,Base Sequence ,biology ,Promoter ,Gene Expression Regulation, Bacterial ,biology.organism_classification ,DNA binding site ,030104 developmental biology ,Biochemistry ,chemistry ,Acetyltransferase ,Acyl Coenzyme A ,Transcription Factors - Abstract
Isovaleryl coenzyme A (IV-CoA) is an important building block of iso-fatty acids. In myxobacteria, IV-CoA is essential for the formation of signaling molecules involved in fruiting body formation. Leucine degradation is the common source of IV-CoA, but a second, de novo biosynthetic route to IV-CoA termed AIB (alternative IV-CoA biosynthesis) was recently discovered in M. xanthus. The AIB-operon contains the TetR-like transcriptional regulator AibR, which we characterize in this study. We demonstrate that IV-CoA binds AibR with micromolar affinity and show by gelshift experiments that AibR interacts with the promoter region of the AIB-operon once IV-CoA is present. We identify an 18-bp near-perfect palindromic repeat as containing the AibR operator and provide evidence that AibR also controls an additional genomic locus coding for a putative acetyl–CoA acetyltransferase. To elucidate atomic details, we determined crystal structures of AibR in the apo, the IV-CoA- and the IV-CoA-DNA-bound state to 1.7 Å, 2.35 Å and 2.92 Å, respectively. IV-CoA induces partial unfolding of an α-helix, which allows sequence-specific interactions between AibR and its operator. This study provides insights into AibR-mediated regulation and shows that AibR functions in an unusual TetR-like manner by blocking transcription not in the ligand-free but in the effector-bound state.
- Published
- 2017
12. Adaptation of a Bacterial Multidrug Resistance System Revealed by the Structure and Function of AlbA
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Katarina Cirnski, Asfandyar Sikandar, Mark Brönstrup, Rolf Müller, Giambattista Testolin, Jesko Koehnke, Carsten Volz, and Olga V. Kalinina
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0301 basic medicine ,Xanthomonas ,medicine.drug_class ,030106 microbiology ,Antibiotics ,Drug resistance ,Plasma protein binding ,Microbial Sensitivity Tests ,medicine.disease_cause ,Biochemistry ,Catalysis ,Microbiology ,Evolution, Molecular ,03 medical and health sciences ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Antibiotic resistance ,Bacterial Proteins ,Drug Resistance, Multiple, Bacterial ,medicine ,Organic Chemicals ,Gene ,Mutation ,Natural product ,Chemistry ,Klebsiella oxytoca ,General Chemistry ,Nitro Compounds ,Anti-Bacterial Agents ,Multiple drug resistance ,030104 developmental biology ,Cyclization ,Asparagine ,Carrier Proteins ,Protein Binding - Abstract
To combat the rise of antimicrobial resistance, the discovery of new antibiotics is paramount. Albicidin and cystobactamid are related natural product antibiotics with potent activity against Gram-positive and, crucially, Gram-negative pathogens. AlbA has been reported to neutralize albicidin by binding it with nanomolar affinity. To understand this potential resistance mechanism, we determined structures of AlbA and its complex with albicidin. The structures revealed AlbA to be comprised of two domains, each unexpectedly resembling the multiantibiotic neutralizing protein TipA. Binding of the long albicidin molecule was shared pseudosymmetrically between the two domains. The structure also revealed an unexpected chemical modification of albicidin, which we demonstrate to be promoted by AlbA, and to reduce albicidin potency; we propose a mechanism for this reaction. Overall, our findings suggest that AlbA arose through internal duplication in an ancient TipA-like gene, leading to a new binding scaffold adapted to the sequestration of long-chain antibiotics.
- Published
- 2018
13. Pinensins: The First Antifungal Lantibiotics
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Judith Hoffmann, Steffen Bernecker, Rolf Jansen, Rolf Müller, Victor Wray, Marc Stadler, Joachim Wink, Carsten Volz, Kathrin I. Mohr, and Klaus Gerth
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chemistry.chemical_classification ,Antifungal Agents ,Gram-negative bacteria ,biology ,Molecular Sequence Data ,General Chemistry ,Ribosomal RNA ,Lantibiotics ,biology.organism_classification ,Catalysis ,chemistry.chemical_compound ,Enzyme ,Bacteriocins ,chemistry ,Biosynthesis ,Biochemistry ,Gene cluster ,Amino Acid Sequence ,Antibacterial activity ,Bacteria - Abstract
Lantibiotics (lanthionine-containing antibiotics) from Gram-positive bacteria typically exhibit activity against Gram-positive bacteria. The activity and structure of pinensin A (1) and B (2), lantibiotics isolated from a native Gram-negative producer Chitinophaga pinensis are described. Surprisingly, the pinensins were found to be highly active against many filamentous fungi and yeasts but show only weak antibacterial activity. To the best of our knowledge, lantibiotic fungicides have not been described before. An in-depth bioinformatic analysis of the biosynthetic gene cluster established the ribosomal origin of these compounds and identified candidate genes encoding all of the enzymes required for post-translational modification. Additional encoded functions enabled us to build up a hypothesis for the biosynthesis, export, sensing, and import of this intriguing lantibiotic.
- Published
- 2015
14. Biosynthesis of Crocacin Involves an Unusual Hydrolytic Release Domain Showing Similarity to Condensation Domains
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Carsten Volz, Shwan Rachid, Nestor Zaburannyi, Rolf Müller, Frank Surup, Thomas Hoffmann, Stefan Müller, and Helmholtz Institute for Pharmaceutical Research Saarland,Saarbru¨ cken, Saarland 66123, Germany.
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Stereochemistry ,Carboxylic acid ,Molecular Sequence Data ,Clinical Biochemistry ,Polyenes ,Cleavage (embryo) ,Models, Biological ,Biochemistry ,chemistry.chemical_compound ,Protein structure ,Myxobacteria ,Biosynthesis ,Gene cluster ,Drug Discovery ,Myxococcales ,Peptide Synthases ,Molecular Biology ,chemistry.chemical_classification ,Pharmacology ,Biological Products ,biology ,Chemistry ,Hydrolysis ,Total synthesis ,General Medicine ,Chain termination ,biology.organism_classification ,Protein Structure, Tertiary ,Multigene Family ,Molecular Medicine ,Genetic Engineering - Abstract
SummaryThe crocacins are potent antifungal and cytotoxic natural compounds from myxobacteria of the genus Chondromyces. Although total synthesis approaches have been reported, the molecular and biochemical basis guiding the formation of the linear crocacin scaffold has remained unknown. Along with the identification and functional analysis of the crocacin biosynthetic gene cluster from Chondromyces crocatus Cm c5, we here present the identification and biochemical characterization of an unusual chain termination domain homologous to condensation domains responsible for hydrolytic release of the product from the assembly line. In particular, gene inactivation studies and in vitro experiments using the heterologously produced domain CroK-C2 confirm this surprising role giving rise to the linear carboxylic acid. Additionally, we determined the kinetic parameters of CroK-C2 by monitoring hydrolytic cleavage of the substrate mimic N-acetylcysteaminyl-crocacin B using an innovative high-performance liquid chromatography mass spectrometry-based assay.
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- 2014
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15. Structure and Biosynthesis of Crocagins: Polycyclic Posttranslationally Modified Ribosomal Peptides from Chondromyces crocatus
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Rolf Müller, Antoine Abou Fayad, Frank Surup, Sebastian Adam, Jennifer Herrmann, Dirk Trauner, Jesko Köhnke, Carsten Volz, and Konrad Viehrig
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Ribosomal Proteins ,Protein Conformation ,Proton Magnetic Resonance Spectroscopy ,Peptide ,010402 general chemistry ,01 natural sciences ,Peptides, Cyclic ,Catalysis ,Mass Spectrometry ,chemistry.chemical_compound ,Biosynthesis ,Bacterial Proteins ,Gene cluster ,Metabolome ,Myxococcales ,Carbon-13 Magnetic Resonance Spectroscopy ,Gene ,chemistry.chemical_classification ,Biological Products ,010405 organic chemistry ,Chemistry ,RNA ,General Chemistry ,Ribosomal RNA ,0104 chemical sciences ,Amino acid ,Biochemistry ,Mutagenesis ,Protein Processing, Post-Translational ,Protein Binding - Abstract
Secondary metabolome mining efforts in the myxobacterial multiproducer of natural products, Chondromyces crocatus Cm c5, resulted in the isolation and structure elucidation of crocagins, which are novel polycyclic peptides containing a tetrahydropyrrolo[2,3-b]indole core. The gene cluster was identified through an approach combining genome analysis, targeted gene inactivation in the producer, and in vitro experiments. Based on our findings, we developed a biosynthetic scheme for crocagin biosynthesis. These natural products are formed from the three C-terminal amino acids of a precursor peptide and thus belong to a novel class of ribosomally synthesized and post-translationally modified peptides (RiPPs). We demonstrate that crocagin A binds to the carbon storage regulator protein CsrA, thereby inhibiting the ability of CsrA to bind to its cognate RNA target.
- Published
- 2016
16. Pinensine: Die ersten antimykotischen Lantibiotika
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Kathrin I. Mohr, Judith Hoffmann, Victor Wray, Rolf Müller, Steffen Bernecker, Rolf Jansen, Joachim Wink, Klaus Gerth, Marc Stadler, Carsten Volz, and Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
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Chemistry ,General Medicine - Published
- 2015
17. Enhancer Binding Proteins Act as Hetero-oligomers and Link Secondary Metabolite Production to Myxococcal Development, Motility, and Predation
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Rolf Müller, Carsten Volz, and Carsten Kegler
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Myxococcus xanthus ,Cellular differentiation ,Clinical Biochemistry ,Molecular Sequence Data ,Motility ,Secondary metabolite ,Biochemistry ,Myxobacteria ,Bacterial Proteins ,Enhancer binding ,Depsipeptides ,Drug Discovery ,medicine ,Promoter Regions, Genetic ,Molecular Biology ,Pharmacology ,Regulation of gene expression ,Genetics ,biology ,Base Sequence ,General Medicine ,Gene Expression Regulation, Bacterial ,biology.organism_classification ,Cell biology ,DNA-Binding Proteins ,Regulon ,Enhancer Elements, Genetic ,Mutation ,Molecular Medicine ,Transcription Initiation Site ,medicine.drug - Abstract
SummaryMotile predatory Myxobacteria are producers of multiple secondary metabolites and, on starvation, undergo concerted cellular differentiation to form multicellular fruiting bodies. These abilities demand myxobacterial genomes to encode sophisticated regulatory networks that are not satisfactorily understood. Here, we present two bacterial enhancer binding proteins (bEBPs) encoded in Myxococcus xanthus acting as direct regulators of secondary metabolites intriguingly exhibiting activating and inhibitory effects. Elucidation of a regulon for each bEBP enabled us to unravel their role in myxococcal development, predation, and motility. Interestingly, both bEBPs are able to interact by forming a hetero-oligomeric complex. Our findings represent an alternative mode of operation of bEBPs, which are currently thought to enhance promoter activity by acting as homo-oligomers. Furthermore, a direct link between secondary metabolite gene expression and predation, motility, and cellular development could be shown for the first time.
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18. Humanitarian coordination in Indonesia: an NGO viewpoint
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Carsten Völz
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forced migration ,refugee ,asylum ,displacement ,disaster ,tsunami ,Indonesia ,Social history and conditions. Social problems. Social reform ,HN1-995 - Abstract
Although the humanitarian community is aware of the value of coordination, field experience in Indonesia in the first few months after the tsunami provides some salutary lessons.
- Published
- 2005
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