26 results on '"Straetener J"'
Search Results
2. Structure of ClpP from Staphylococcus aureus (apo, closed state)
- Author
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Malik, I.T., primary, Pereira, R., additional, Vielberg, M.-T., additional, Mayer, C., additional, Straetener, J., additional, Thomy, D., additional, Famulla, K., additional, Castro, H.C., additional, Sass, P., additional, Groll, M., additional, and Broetz-Oesterheldt, H., additional
- Published
- 2020
- Full Text
- View/download PDF
3. Structure of the ClpP:ADEP4-complex from Staphylococcus aureus (open state)
- Author
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Malik, I.T., primary, Pereira, R., additional, Vielberg, M.-T., additional, Mayer, C., additional, Straetener, J., additional, Thomy, D., additional, Famulla, K., additional, Castro, H.C., additional, Sass, P., additional, Groll, M., additional, and Broetz-Oesterheldt, H., additional
- Published
- 2020
- Full Text
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4. Exocrine AR42J acinar cells enhance viability of cocultured endocrine INS-1E beta cells
- Author
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Peradze, N, additional, Straetener, J, additional, Zhang, W, additional, Liu, F, additional, Laubner, K, additional, Perakakis, N, additional, Seufert, J, additional, and Päth, G, additional
- Published
- 2017
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5. Mesenchymal Stem Cell (MSC)-derived humoral factors promote survival of insulin producing pancreatic β-cells during intrinsic cellular stress via Akt and ERK1/2 signalling
- Author
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Zhang, W, additional, Liu, C, additional, Peradze, N, additional, Straetener, J, additional, Laubner, K, additional, Perakakis, N, additional, Seufert, J, additional, and Päth, G, additional
- Published
- 2017
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6. Insulinabgabegenauigkeiten von Patch-Pumpen versus Schlauchpumpen – Eine systematische Analyse unter Laborbedingungen
- Author
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Singler, E, primary, Siegmund, T, additional, Päth, G, additional, Hruby, B, additional, Tränkle, S, additional, Straetener, J, additional, Hille, M, additional, Kriedemann, D, additional, Seufert, J, additional, and Laubner, K, additional
- Published
- 2016
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7. Mesenchymal stem cell (MSC)-mediated activation of ERK1/2 signaling does not contribute to maintained survival of cocultured alloxan-treated INS-1E beta cells
- Author
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Zhang, W, primary, Peradze, N, additional, Liu, F, additional, Straetener, J, additional, Laubner, K, additional, Perakakis, N, additional, Seufert, J, additional, and Päth, G, additional
- Published
- 2016
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8. Preserved insulin response of Nupr1-transgenic islets during diabetogenic injury is correlated with reduced secretion of IL-1beta and enhanced secretion of IL-1 receptor antagonist
- Author
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Mehana, AE, primary, Straetener, J, additional, Baumann, J, additional, Perakakis, N, additional, Laubner, K, additional, Seufert, J, additional, and Päth, G, additional
- Published
- 2015
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9. The macrophage migration inhibitory factor (MIF)/CXCR4 axis regulates migration of bone marrow derived mesenchymal stem cells towards pancreatic ß-cells under lipotoxic conditions
- Author
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Mihic-Necic, B, primary, Taromi, S, additional, Liu, C, additional, Straetener, J, additional, Ihle, M, additional, Kriedemann, D, additional, Hille, M, additional, Mehana, AE, additional, Laubner, K, additional, Perakakis, N, additional, Päth, G, additional, and Seufert, J, additional
- Published
- 2015
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10. Ticagrelor alters the membrane of Staphylococcus aureus and enhances the activity of vancomycin and daptomycin without eliciting cross-resistance.
- Author
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Leeten K, Jacques N, Esquembre LA, Schneider DC, Straetener J, Henriksen C, Musumeci L, Putters F, Melo S, Sánchez-López E, Giera M, Penoy N, Piel G, Verlaine O, Amoroso A, Joris B, Slavetinsky CJ, Goffin E, Pirotte B, Frees D, Brötz-Oesterhelt H, Lancellotti P, and Oury C
- Subjects
- Bacillus subtilis drug effects, Bacillus subtilis genetics, Methicillin-Resistant Staphylococcus aureus drug effects, Methicillin-Resistant Staphylococcus aureus genetics, Drug Synergism, Drug Resistance, Multiple, Bacterial, Humans, Daptomycin pharmacology, Vancomycin pharmacology, Anti-Bacterial Agents pharmacology, Ticagrelor pharmacology, Microbial Sensitivity Tests, Cell Membrane drug effects, Staphylococcus aureus drug effects, Staphylococcus aureus genetics
- Abstract
Infections with multidrug-resistant bacteria pose a major healthcare problem which urges the need for novel treatment options. Besides its potent antiplatelet properties, ticagrelor has antibacterial activity against Gram-positive bacteria, including methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA). Several retrospective studies in cardiovascular patients support an antibacterial effect of this drug which is not related to its antiplatelet activity. We investigated the mechanism of action of ticagrelor in Staphylococcus aureus and model Bacillus subtilis, and assessed cross-resistance with two conventional anti-MRSA antibiotics, vancomycin and daptomycin. Bacillus subtilis bioreporter strains revealed ticagrelor-induced cell envelope-related stress responses. Sub-inhibitory drug concentrations caused membrane depolarization, impaired positioning of both the peripheral membrane protein MinD and the peptidoglycan precursor lipid II, and it affected cell shape. At the MIC, ticagrelor destroyed membrane integrity, indicated by the influx of membrane impermeable dyes, and lipid aggregate formation. Whole-genome sequencing of in vitro -generated ticagrelor-resistant MRSA clones revealed mutations in genes encoding ClpP, ClpX, and YjbH. Lipidomic analysis of resistant clones displayed changes in levels of the most abundant lipids of the Staphylococcus aureus membrane, for example, cardiolipins, phosphatidylglycerols, and diacylglycerols. Exogeneous cardiolipin, phosphatidylglycerol, or diacylglycerol antagonized the antibacterial properties of ticagrelor. Ticagrelor enhanced MRSA growth inhibition and killing by vancomycin and daptomycin in both exponential and stationary phases. Finally, no cross-resistance was observed between ticagrelor and daptomycin, or vancomycin. Our study demonstrates that ticagrelor targets multiple lipids in the cytoplasmic membrane of Gram-positive bacteria, thereby retaining activity against multidrug-resistant staphylococci including daptomycin- and vancomycin-resistant strains.IMPORTANCEInfections with multidrug-resistant bacteria pose a major healthcare problem with an urgent need for novel treatment options. The antiplatelet drug ticagrelor possesses antibacterial activity against Gram-positive bacteria including methicillin-resistant and vancomycin-resistant Staphylococcus aureus strains. We report a unique, dose-dependent, antibacterial mechanism of action of ticagrelor, which alters the properties and integrity of the bacterial cytoplasmic membrane. Ticagrelor retains activity against multidrug-resistant staphylococci, including isolates carrying the most common in vivo selected daptomycin resistance mutations and vancomycin-intermediate Staphylococcus aureus . Our data support the use of ticagrelor as adjunct therapy against multidrug-resistant strains. Because of the presence of multiple non-protein targets of this drug within the bacterial membrane, resistance development is expected to be slow. All these findings corroborate the accumulating observational clinical evidence for a beneficial anti-bacterial effect of ticagrelor in cardiovascular patients in need of such treatment., Competing Interests: The authors declare no conflict of interest.
- Published
- 2024
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11. The Dual Mode of Antibacterial Action of the Synthetic Small Molecule DCAP Involves Lipid II Binding.
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Ludwig KC, Puls JS, Matos de Opitz CL, Innocenti P, Daniel JM, Bornikoel J, Arts M, Krannich S, Straetener J, Brajtenbach D, Henrichfreise B, Sass P, Mueller A, Martin NI, Brötz-Oesterhelt H, Kubitscheck U, Grein F, and Schneider T
- Subjects
- Molecular Structure, Cell Wall drug effects, Cell Wall metabolism, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Small Molecule Libraries chemical synthesis, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents chemical synthesis, Uridine Diphosphate N-Acetylmuramic Acid analogs & derivatives, Uridine Diphosphate N-Acetylmuramic Acid metabolism, Uridine Diphosphate N-Acetylmuramic Acid chemistry, Microbial Sensitivity Tests
- Abstract
The synthetic small molecule DCAP is a chemically well-characterized compound with antibiotic activity against Gram-positive and Gram-negative bacteria, including drug-resistant pathogens. Until now, its mechanism of action was proposed to rely exclusively on targeting the bacterial membrane, thereby causing membrane depolarization, and increasing membrane permeability (Eun et al. 2012, J. Am. Chem. Soc. 134 (28), 11322-11325; Hurley et al. 2015, ACS Med. Chem. Lett. 6, 466-471). Here, we show that the antibiotic activity of DCAP results from a dual mode of action that is more targeted and multifaceted than previously anticipated. Using microbiological and biochemical assays in combination with fluorescence microscopy, we provide evidence that DCAP interacts with undecaprenyl pyrophosphate-coupled cell envelope precursors, thereby blocking peptidoglycan biosynthesis and impairing cell division site organization. Our work discloses a concise model for the mode of action of DCAP which involves the binding to a specific target molecule to exert pleiotropic effects on cell wall biosynthetic and divisome machineries.
- Published
- 2024
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12. The microbiome-derived antibacterial lugdunin acts as a cation ionophore in synergy with host peptides.
- Author
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Berscheid A, Straetener J, Schilling NA, Ruppelt D, Konnerth MC, Schittek B, Krismer B, Peschel A, Steinem C, Grond S, and Brötz-Oesterhelt H
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- Humans, Cations pharmacology, Cations metabolism, Drug Synergism, Lipopeptides pharmacology, Lipopeptides metabolism, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Ionophores pharmacology, Microbiota drug effects, Staphylococcus aureus drug effects, Staphylococcus aureus metabolism
- Abstract
Lugdunin is a microbiome-derived antibacterial agent with good activity against Gram-positive pathogens in vitro and in animal models of nose colonization and skin infection. We have previously shown that lugdunin depletes bacterial energy resources by dissipating the membrane potential of Staphylococcus aureus . Here, we explored the mechanism of action of lugdunin in more detail and show that lugdunin quickly depolarizes cytoplasmic membranes of different bacterial species and acidifies the cytoplasm of S. aureus within minutes due to protonophore activity. Varying the salt species and concentrations in buffers revealed that not only protons are transported, and we demonstrate the binding of the monovalent cations K
+ , Na+ , and Li+ to lugdunin. By comparing known ionophores with various ion transport mechanisms, we conclude that the ion selectivity of lugdunin largely resembles that of 15-mer linear peptide gramicidin A. Direct interference with the main bacterial metabolic pathways including DNA, RNA, protein, and cell wall biosyntheses can be excluded. The previously observed synergism of lugdunin with dermcidin-derived peptides such as DCD-1 in killing S. aureus is mechanistically based on potentiated membrane depolarization. We also found that lugdunin was active against certain eukaryotic cells, however strongly depending on the cell line and growth conditions. While adherent lung epithelial cell lines were almost unaffected, more sensitive cells showed dissipation of the mitochondrial membrane potential. Lugdunin seems specifically adapted to its natural environment in the respiratory tract. The ionophore mechanism is refractory to resistance development and benefits from synergy with host-derived antimicrobial peptides., Importance: The vast majority of antimicrobial peptides produced by members of the microbiome target the bacterial cell envelope by many different mechanisms. These compounds and their producers have evolved side-by-side with their host and were constantly challenged by the host's immune system. These molecules are optimized to be well tolerated at their physiological site of production, and their modes of action have proven efficient in vivo . Imbalancing the cellular ion homeostasis is a prominent mechanism among antibacterial natural products. For instance, over 120 naturally occurring polyether ionophores are known to date, and antimicrobial peptides with ionophore activity have also been detected in microbiomes. In this study, we elucidated the mechanism underlying the membrane potential-dissipating activity of the thiazolidine-containing cycloheptapeptide lugdunin, the first member of the fibupeptides discovered in a commensal bacterium from the human nose, which is a promising future probiotic candidate that is not prone to resistance development., Competing Interests: The authors declare no conflict of interest.- Published
- 2024
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13. Antibacterial Marinopyrroles and Pseudilins Act as Protonophores.
- Author
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Castro-Falcón G, Straetener J, Bornikoel J, Reimer D, Purdy TN, Berscheid A, Schempp FM, Liu DY, Linington RG, Brötz-Oesterhelt H, and Hughes CC
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Pyrroles pharmacology, Microbial Sensitivity Tests, Mammals, Hydrocarbons, Chlorinated, Biological Products
- Abstract
Elucidating the mechanism of action (MoA) of antibacterial natural products is crucial to evaluating their potential as novel antibiotics. Marinopyrroles, pentachloropseudilin, and pentabromopseudilin are densely halogenated, hybrid pyrrole-phenol natural products with potent activity against Gram-positive bacterial pathogens like Staphylococcus aureus . However, the exact way they exert this antibacterial activity has not been established. In this study, we explore their structure-activity relationship, determine their spatial location in bacterial cells, and investigate their MoA. We show that the natural products share a common MoA based on membrane depolarization and dissipation of the proton motive force (PMF) that is essential for cell viability. The compounds show potent protonophore activity but do not appear to destroy the integrity of the cytoplasmic membrane via the formation of larger pores or interfere with the stability of the peptidoglycan sacculus. Thus, our current model for the antibacterial MoA of marinopyrrole, pentachloropseudilin, and pentabromopseudilin stipulates that the acidic compounds insert into the membrane and transport protons inside the cell. This MoA may explain many of the deleterious biological effects in mammalian cells, plants, phytoplankton, viruses, and protozoans that have been reported for these compounds.
- Published
- 2024
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14. Bioinformatics-guided discovery of biaryl-linked lasso peptides.
- Author
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Saad H, Majer T, Bhattarai K, Lampe S, Nguyen DT, Kramer M, Straetener J, Brötz-Oesterhelt H, Mitchell DA, and Gross H
- Abstract
Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) that feature an isopeptide bond and a distinct lariat fold. A growing number of secondary modifications have been described that further decorate lasso peptide scaffolds. Using genome mining, we have discovered a pair of lasso peptide biosynthetic gene clusters (BGCs) that include cytochrome P450 genes. Using mass spectrometry, stable isotope incorporation, and extensive 2D-NMR spectrometry, we report the structural characterization of two unique examples of (C-N) biaryl-linked lasso peptides. Nocapeptin A, from Nocardia terpenica , is tailored with a Trp-Tyr crosslink, while longipepetin A, from Longimycelium tulufanense , features a Trp-Trp linkage. Besides the unusual bicyclic frame, a Met of longipepetin A undergoes S -methylation to yield a trivalent sulfonium, a heretofore unprecedented RiPP modification. A bioinformatic survey revealed additional lasso peptide BGCs containing P450 enzymes which await future characterization. Lastly, nocapeptin A bioactivity was assessed against a panel of human and bacterial cell lines with modest growth-suppression activity detected towards Micrococcus luteus ., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)
- Published
- 2023
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15. Bioinformatics-Guided Discovery of Biaryl-Tailored Lasso Peptides.
- Author
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Saad H, Majer T, Bhattarai K, Lampe S, Nguyen DT, Kramer M, Straetener J, Brötz-Oesterhelt H, Mitchell DA, and Gross H
- Abstract
Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) that feature an isopeptide bond and a distinct lariat fold. A growing number of secondary modifications have been described that further decorate lasso peptide scaffolds. Using genome mining, we have discovered a pair of lasso peptide biosynthetic gene clusters (BGCs) that include cytochrome P450 genes. Here, we report the structural characterization of two unique examples of (C-N) biaryl-containing lasso peptides. Nocapeptin A, from Nocardia terpenica, is tailored with Trp-Tyr crosslink while longipepetin A, from Longimycelium tulufanense, features Trp-Trp linkage. Besides the unusual bicyclic frame, longipepetin A receives an S-methylation by a new Met methyltransferase resulting in unprecedented sulfonium-bearing RiPP. Our bioinformatic survey revealed P450(s) and further maturating enzyme(s)-containing lasso BGCs awaiting future characterization.
- Published
- 2023
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16. The Cyanobacterial "Nutraceutical" Phycocyanobilin Inhibits Cysteine Protease Legumain.
- Author
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Wilkinson IVL, Castro-Falcón G, Roda-Serrat MC, Purdy TN, Straetener J, Brauny MM, Maier L, Brötz-Oesterhelt H, Christensen LP, Sieber SA, and Hughes CC
- Subjects
- Phycocyanin pharmacology, Phycocyanin chemistry, Phycobilins pharmacology, Phycobilins chemistry, Dietary Supplements, Cysteine Proteases, Spirulina chemistry
- Abstract
The blue biliprotein phycocyanin, produced by photo-autotrophic cyanobacteria including spirulina (Arthrospira) and marketed as a natural food supplement or "nutraceutical," is reported to have anti-inflammatory, antioxidant, immunomodulatory, and anticancer activity. These diverse biological activities have been specifically attributed to the phycocyanin chromophore, phycocyanobilin (PCB). However, the mechanism of action of PCB and the molecular targets responsible for the beneficial properties of PCB are not well understood. We have developed a procedure to rapidly cleave the PCB pigment from phycocyanin by ethanolysis and then characterized it as an electrophilic natural product that interacts covalently with thiol nucleophiles but lacks any appreciable cytotoxicity or antibacterial activity against common pathogens and gut microbes. We then designed alkyne-bearing PCB probes for use in chemical proteomics target deconvolution studies. Target identification and validation revealed the cysteine protease legumain (also known as asparaginyl endopeptidase, AEP) to be a target of PCB. Inhibition of this target may account for PCB's diverse reported biological activities., (© 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.)
- Published
- 2023
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17. Discovery of Ircinianin Lactones B and C-Two New Cyclic Sesterterpenes from the Marine Sponge Ircinia wistarii .
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Majer T, Bhattarai K, Straetener J, Pohlmann J, Cahill P, Zimmermann MO, Hübner MP, Kaiser M, Svenson J, Schindler M, Brötz-Oesterhelt H, Boeckler FM, and Gross H
- Subjects
- Animals, Lactones chemistry, Lactones pharmacology, Molecular Structure, Terpenes pharmacology, Porifera chemistry, Sesterterpenes chemistry, Sesterterpenes pharmacology
- Abstract
Two new ircinianin-type sesterterpenoids, ircinianin lactone B and ircinianin lactone C ( 7 and 8 ), together with five known entities from the ircinianin compound family ( 1 , 3 - 6 ) were isolated from the marine sponge Ircinia wistarii . Ircinianin lactones B and C ( 7 and 8 ) represent new ircinianin terpenoids with a modified oxidation pattern. Despite their labile nature, the structures could be established using a combination of spectroscopic data, including HRESIMS and 1D/2D NMR techniques, as well as computational chemistry and quantum-mechanical calculations. In a broad screening approach for biological activity, the class-defining compound ircinianin ( 1 ) showed moderate antiprotozoal activity against Plasmodium falciparum (IC
50 25.4 μM) and Leishmania donovani (IC50 16.6 μM).- Published
- 2022
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18. Synergetic Antimicrobial Activity and Mechanism of Clotrimazole-Linked CO-Releasing Molecules.
- Author
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Mendes SS, Marques J, Mesterházy E, Straetener J, Arts M, Pissarro T, Reginold J, Berscheid A, Bornikoel J, Kluj RM, Mayer C, Oesterhelt F, Friães S, Royo B, Schneider T, Brötz-Oesterhelt H, Romão CC, and Saraiva LM
- Abstract
Several metal-based carbon monoxide-releasing molecules (CORMs) are active CO donors with established antibacterial activity. Among them, CORM conjugates with azole antibiotics of type [Mn(CO)
3 (2,2'-bipyridyl)(azole)]+ display important synergies against several microbes. We carried out a structure-activity relationship study based upon the lead structure of [Mn(CO)3 (Bpy)(Ctz)]+ by producing clotrimazole (Ctz) conjugates with varying metal and ligands. We concluded that the nature of the bidentate ligand strongly influences the bactericidal activity, with the substitution of bipyridyl by small bicyclic ligands leading to highly active clotrimazole conjugates. On the contrary, the metal did not influence the activity. We found that conjugate [Re(CO)3 (Bpy)(Ctz)]+ is more than the sum of its parts: while precursor [Re(CO)3 (Bpy)Br] has no antibacterial activity and clotrimazole shows only moderate minimal inhibitory concentrations, the potency of [Re(CO)3 (Bpy)(Ctz)]+ is one order of magnitude higher than that of clotrimazole, and the spectrum of bacterial target species includes Gram-positive and Gram-negative bacteria. The addition of [Re(CO)3 (Bpy)(Ctz)]+ to Staphylococcus aureus causes a general impact on the membrane topology, has inhibitory effects on peptidoglycan biosynthesis, and affects energy functions. The mechanism of action of this kind of CORM conjugates involves a sequence of events initiated by membrane insertion, followed by membrane disorganization, inhibition of peptidoglycan synthesis, CO release, and break down of the membrane potential. These results suggest that conjugation of CORMs to known antibiotics may produce useful structures with synergistic effects that increase the conjugate's activity relative to that of the antibiotic alone., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)- Published
- 2022
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19. High Plasticity of the Amicetin Biosynthetic Pathway in Streptomyces sp. SHP 22-7 Led to the Discovery of Streptcytosine P and Cytosaminomycins F and G and Facilitated the Production of 12F-Plicacetin.
- Author
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Aryal N, Chen J, Bhattarai K, Hennrich O, Handayani I, Kramer M, Straetener J, Wommer T, Berscheid A, Peter S, Reiling N, Brötz-Oesterhelt H, Geibel C, Lämmerhofer M, Mast Y, and Gross H
- Subjects
- Biosynthetic Pathways, Disaccharides, Molecular Structure, Nucleosides, Pyrimidine Nucleosides chemistry, Streptomyces chemistry
- Abstract
A chemical reinvestigation of the Indonesian strain Streptomyces sp. SHP 22-7 led to the isolation of three new pyrimidine nucleosides, along with six known analogues and zincphyrin. The structures of the new compounds ( 6 , 7 , 10 ) were elucidated by employing spectroscopic techniques (NMR, MS, CD, and IR) as well as enantioselective analyses of methyl branched side chain configurations. Application of the precursor-directed feeding approach led to the production and partial isolation of nine further pyrimidine analogues. The new compounds 6 , 7 , and 11 and three of the known compounds ( 2 - 4 ) were found to possess antimycobacterial and cytotoxic properties.
- Published
- 2022
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20. Nocathioamides, Uncovered by a Tunable Metabologenomic Approach, Define a Novel Class of Chimeric Lanthipeptides.
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Saad H, Aziz S, Gehringer M, Kramer M, Straetener J, Berscheid A, Brötz-Oesterhelt H, and Gross H
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- Alanine chemistry, Computational Biology, Data Mining, Genome, Bacterial, Isotopes chemistry, Magnetic Resonance Spectroscopy, Multigene Family, Protein Conformation, Protein Processing, Post-Translational, Ribosomes metabolism, Tandem Mass Spectrometry, Thioamides chemistry, Alanine analogs & derivatives, Nocardia chemistry, Peptides chemistry, Sulfides chemistry
- Abstract
The increasing number of available genomes, in combination with advanced genome mining techniques, unveiled a plethora of biosynthetic gene clusters (BGCs) coding for ribosomally synthesized and post-translationally modified peptides (RiPPs). The products of these BGCs often represent an enormous resource for new and bioactive compounds, but frequently, they cannot be readily isolated and remain cryptic. Here, we describe a tunable metabologenomic approach that recruits a synergism of bioinformatics in tandem with isotope- and NMR-guided platform to identify the product of an orphan RiPP gene cluster in the genomes of Nocardia terpenica IFM 0406 and 0706
T . The application of this tactic resulted in the discovery of nocathioamides family as a founder of a new class of chimeric lanthipeptides I., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)- Published
- 2021
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21. Massiliamide, a cyclic tetrapeptide with potent tyrosinase inhibitory properties from the Gram-negative bacterium Massilia albidiflava DSM 17472 T .
- Author
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Frediansyah A, Straetener J, Brötz-Oesterhelt H, and Gross H
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- Drug Evaluation, Preclinical, Enzyme Inhibitors chemistry, HeLa Cells, Humans, Nuclear Magnetic Resonance, Biomolecular, Peptides, Cyclic isolation & purification, Spectrometry, Mass, Electrospray Ionization, Enzyme Inhibitors pharmacology, Monophenol Monooxygenase antagonists & inhibitors, Oxalobacteraceae chemistry, Peptides, Cyclic chemistry, Peptides, Cyclic pharmacology
- Abstract
A cyclic tetrapeptide, designated massiliamide, was isolated from the liquid culture of the Gram-negative bacterium Massilia albidiflava DSM 17472
T . The structure was elucidated through extensive spectroscopic analysis, including HR-MS and 1D and 2D NMR experiments. The absolute configuration was determined using the Marfey´s method. Massiliamide showed potent inhibitory activity towards tyrosinase with an IC50 value of 1.15 µM and no cytotoxicity.- Published
- 2021
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22. New Nocobactin Derivatives with Antimuscarinic Activity, Terpenibactins A-C, Revealed by Genome Mining of Nocardia terpenica IFM 0406.
- Author
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Chen J, Frediansyah A, Männle D, Straetener J, Brötz-Oesterhelt H, Ziemert N, Kaysser L, and Gross H
- Subjects
- Computer Simulation, Multigene Family genetics, Muscarinic Antagonists pharmacology, Nocardia metabolism, Oxazoles pharmacology, Data Mining, Genomics, Muscarinic Antagonists chemistry, Muscarinic Antagonists metabolism, Nocardia genetics, Oxazoles chemistry, Oxazoles metabolism
- Abstract
We report a genomics-guided exploration of the metabolic potential of the brasilicardin producer strain Nocardia terpenica IFM 0406. Bioinformatics analysis of the whole genome sequence revealed the presence of a biosynthetic gene cluster presumably responsible for the generation of formerly unknown nocobactin derivatives. Mass spectrometry-assisted isolation led to the identification of three new siderophores, terpenibactins A (1), B (2) and C (3), which belong to the class of nocobactins. Their structures were elucidated by employing spectroscopic techniques. Compounds 1-3 demonstrated inhibitory activity towards the muscarinic M3 receptor, while exhibiting only a low cytotoxicity., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)
- Published
- 2020
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23. Functional Characterisation of ClpP Mutations Conferring Resistance to Acyldepsipeptide Antibiotics in Firmicutes.
- Author
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Malik IT, Pereira R, Vielberg MT, Mayer C, Straetener J, Thomy D, Famulla K, Castro H, Sass P, Groll M, and Brötz-Oesterhelt H
- Subjects
- Anti-Bacterial Agents chemistry, Depsipeptides chemistry, Endopeptidase Clp metabolism, Firmicutes enzymology, Microbial Sensitivity Tests, Molecular Conformation, Mutation, Staphylococcus aureus enzymology, Anti-Bacterial Agents pharmacology, Depsipeptides pharmacology, Drug Resistance, Bacterial drug effects, Endopeptidase Clp antagonists & inhibitors, Firmicutes drug effects, Staphylococcus aureus drug effects
- Abstract
Acyldepsipeptide (ADEP) is an exploratory antibiotic with a novel mechanism of action. ClpP, the proteolytic core of the caseinolytic protease, is deregulated towards unrestrained proteolysis. Here, we report on the mechanism of ADEP resistance in Firmicutes. This bacterial phylum contains important pathogens that are relevant for potential ADEP therapy. For Staphylococcus aureus, Bacillus subtilis, enterococci and streptococci, spontaneous ADEP-resistant mutants were selected in vitro at a rate of 10
-6 . All isolates carried mutations in clpP. All mutated S. aureus ClpP proteins characterised in this study were functionally impaired; this increased our understanding of the mode of operation of ClpP. For molecular insights, crystal structures of S. aureus ClpP bound to ADEP4 were determined. Well-resolved N-terminal domains in the apo structure allow the pore-gating mechanism to be followed. The compilation of mutations presented here indicates residues relevant for ClpP function and suggests that ADEP resistance will occur at a lower rate during the infection process., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)- Published
- 2020
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24. Nostotrebin 6 Related Cyclopentenediones and δ-Lactones with Broad Activity Spectrum Isolated from the Cultivation Medium of the Cyanobacterium Nostoc sp. CBT1153.
- Author
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Kossack R, Breinlinger S, Nguyen T, Moschny J, Straetener J, Berscheid A, Brötz-Oesterhelt H, Enke H, Schirmeister T, and Niedermeyer THJ
- Subjects
- Anti-Bacterial Agents isolation & purification, Culture Media, Cyclopentanes isolation & purification, Molecular Structure, Nostoc chemistry, Anti-Bacterial Agents chemistry, Cyclopentanes chemistry, Lactones chemistry, Phenols chemistry
- Abstract
Cyanobacteria are an interesting source of biologically active natural products, especially chemically diverse and potent protease inhibitors. On our search for inhibitors of the trypanosomal cysteine protease rhodesain, we identified the homodimeric cyclopentenedione (CPD) nostotrebin 6 ( 1 ) and new related monomeric, dimeric, and higher oligomeric compounds as the active substances in the medium extract of Nostoc sp. CBT1153. The oligomeric compounds are composed of two core monomeric structures, a trisubstituted CPD or a trisubstituted unsaturated δ-lactone. Nostotrebin 6 thus far has been the only known cyanobacterial CPD. It has been found to be active in a broad variety of assays, indicating that it might be a pan-assay interference compound (PAIN). Thus, we compared the antibacterial and cytotoxic activities as well as the rhodesain inhibition of selected compounds. Because a compound with a δ-lactone instead of a CPD core structure was equally active as nostotrebin 6, the bioactivities of these compounds seem to be based on the phenolic substructures rather than the CPD moiety. While the dimers were roughly equally potent, the monomer displayed slightly weaker activity, suggesting that the compounds show unspecific activity depending upon the number of free phenolic hydroxy groups per molecule.
- Published
- 2020
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25. Comparative Dose Accuracy of Durable and Patch Insulin Pumps Under Laboratory Conditions.
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Laubner K, Singler E, Straetener J, Siegmund T, Päth G, and Seufert J
- Subjects
- Diabetes Mellitus drug therapy, Dose-Response Relationship, Drug, Humans, Durable Medical Equipment, Hypoglycemic Agents administration & dosage, Insulin administration & dosage, Insulin Infusion Systems, Transdermal Patch
- Abstract
Background: Recent studies demonstrate variable results of the accuracy with which patch pumps infuse insulin. Aim of this evaluation was to measure dose accuracies of the patch pump mylife™ OmniPod
® (OP) in comparison with the durable insulin pump MiniMed® 640G (MM) simulating real-life clinical situations under laboratory conditions. Methods: Thirty-two OP and 15 MM were tested using insulin aspart at five different boluses (0.5, 1, 5, 10, and 15 international units [IU]) and three basal rates (0.2, 0.6, and 1.8 IU/h) at different time points during a 70 h investigation period. Owing to malfunctions only 22 OP and 11 MM could be analyzed. Dose accuracy was measured by an experimental setting based on IEC 60601-2-24:2012 with determination of weight differences of insulin collection tubes before and after experiments using a precision scale. A maximal tolerance of ±5% for boluses and basal rates was considered adequate according to IEC 60601-2-24:2012. Results: For the five boluses, the percentages of measurement results within the ±5% accuracy threshold were as follows: OP (18.6%, 26.5%, 89.0%, 96.0%, and 96.0%); MM (21.7%, 44.1%, 88.1%, 98.3%, and 100.0%). Both pumps were more accurate at higher bolus volumes (5, 10, and 15 IU), later bolus periods, and if the accuracy threshold was lowered to <10%, <15%, or >15%. For the three basal rates, the percentages within the ±5% accuracy threshold were as follows: OP (66.7%, 22.7%, and 16.7%); MM (14.3%, 0.0%, and 0.0%). Conclusion: This study demonstrates low accuracy for basal rates and single bolus deliveries at low insulin doses for both pump models. Clinicians should be aware of this variability when initiating insulin pump therapy especially in insulin-sensitive patients with low insulin dose requirements.- Published
- 2019
- Full Text
- View/download PDF
26. Mesenchymal stem cell (MSC)-mediated survival of insulin producing pancreatic β-cells during cellular stress involves signalling via Akt and ERK1/2.
- Author
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Liu C, Zhang W, Peradze N, Lang L, Straetener J, Feilen PJ, Alt M, Jäger C, Laubner K, Perakakis N, Seufert J, and Päth G
- Subjects
- Alloxan, Animals, Caspase 3 metabolism, Caspase 7 metabolism, Cell Movement drug effects, Cell Survival drug effects, Cytoprotection drug effects, Humans, Interleukin-1beta pharmacology, Mice, Inbred C57BL, NF-kappa B metabolism, Phosphorylation drug effects, Poly(ADP-ribose) Polymerases metabolism, Rats, Wistar, Streptozocin, Telomerase metabolism, Insulin biosynthesis, Insulin-Secreting Cells enzymology, Insulin-Secreting Cells pathology, MAP Kinase Signaling System drug effects, Mesenchymal Stem Cells cytology, Proto-Oncogene Proteins c-akt metabolism, Stress, Physiological drug effects
- Abstract
Mesenchymal stem cells (MSC) are of interest for cell therapy since their secreted factors mediate immunomodulation and support tissue regeneration. This study investigated the direct humoral interactions between MSC and pancreatic β-cells using human telomerase-immortalized MSC (hMSC-TERT) and rat insulinoma-derived INS-1E β-cells. hMSC-TERT supported survival of cocultured INS-1E β-cells during cellular stress by alloxan (ALX) and streptozotocin (STZ), but not in response to IL-1β. Accordingly, hMSC-TERT had no effect on inflammatory cytokine-related signalling via NF-kB and p-JNK but maintained p-Akt and upregulated p-ERK1/2. Inhibition of either p-Akt or p-ERK1/2 did not abolish protection by hMSC-TERT but activated the respective non-inhibited pathway. This suggests that one pathway compensates for the other. Main results were confirmed in mouse islets except hMSC-TERT-mediated upregulation of p-ERK1/2. Therefore, MSC promote β-cell survival by preservation of p-Akt signalling and further involve p-ERK1/2 activation in certain conditions such as loss of p-Akt or insulinoma background., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
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