25 results on '"Eva Zborníková"'
Search Results
2. Novel (p)ppGpp Binding and Metabolizing Proteins of Escherichia coli
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Yong Zhang, Eva Zborníková, Dominik Rejman, and Kenn Gerdes
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(p)ppGpp ,DRaCALA ,GTPase ,Nudix ,multidrug tolerance ,persistence ,Microbiology ,QR1-502 - Abstract
ABSTRACT The alarmone (p)ppGpp plays pivotal roles in basic bacterial stress responses by increasing tolerance of various nutritional limitations and chemical insults, including antibiotics. Despite intensive studies since (p)ppGpp was discovered over 4 decades ago, (p)ppGpp binding proteins have not been systematically identified in Escherichia coli. We applied DRaCALA (differential radial capillary action of ligand assay) to identify (p)ppGpp-protein interactions. We discovered 12 new (p)ppGpp targets in E. coli that, based on their physiological functions, could be classified into four major groups, involved in (i) purine nucleotide homeostasis (YgdH), (ii) ribosome biogenesis and translation (RsgA, Era, HflX, and LepA), (iii) maturation of dehydrogenases (HypB), and (iv) metabolism of (p)ppGpp (MutT, NudG, TrmE, NadR, PhoA, and UshA). We present a comprehensive and comparative biochemical and physiological characterization of these novel (p)ppGpp targets together with a comparative analysis of relevant, known (p)ppGpp binding proteins. Via this, primary targets of (p)ppGpp in E. coli are identified. The GTP salvage biosynthesis pathway and ribosome biogenesis and translation are confirmed as targets of (p)ppGpp that are highly conserved between E. coli and Firmicutes. In addition, an alternative (p)ppGpp degradative pathway, involving NudG and MutT, was uncovered. This report thus significantly expands the known cohort of (p)ppGpp targets in E. coli. IMPORTANCE Antibiotic resistance and tolerance exhibited by pathogenic bacteria have resulted in a global public health crisis. Remarkably, almost all bacterial pathogens require the alarmone (p)ppGpp to be virulent. Thus, (p)ppGpp not only induces tolerance of nutritional limitations and chemical insults, including antibiotics, but is also often required for induction of virulence genes. However, understanding of the molecular targets of (p)ppGpp and the mechanisms by which (p)ppGpp influences bacterial physiology is incomplete. In this study, a systematic approach was used to uncover novel targets of (p)ppGpp in E. coli, the best-studied model bacterium. Comprehensive comparative studies of the targets revealed conserved target pathways of (p)ppGpp in both Gram-positive and -negative bacteria and novel targets of (p)ppGpp, including an alternative degradative pathway of (p)ppGpp. Thus, our discoveries may help in understanding of how (p)ppGpp increases the stress resilience and multidrug tolerance not only of the model organism E. coli but also of the pathogenic organisms in which these targets are conserved.
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- 2018
- Full Text
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3. Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins.
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Natalya Panova, Eva Zborníková, Ondřej Šimák, Radek Pohl, Milan Kolář, Kateřina Bogdanová, Renata Večeřová, Gabriela Seydlová, Radovan Fišer, Romana Hadravová, Hana Šanderová, Dragana Vítovská, Michaela Šiková, Tomáš Látal, Petra Lovecká, Ivan Barvík, Libor Krásný, and Dominik Rejman
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Medicine ,Science - Abstract
The advantages offered by established antibiotics in the treatment of infectious diseases are endangered due to the increase in the number of antibiotic-resistant bacterial strains. This leads to a need for new antibacterial compounds. Recently, we discovered a series of compounds termed lipophosphonoxins (LPPOs) that exhibit selective cytotoxicity towards Gram-positive bacteria that include pathogens and resistant strains. For further development of these compounds, it was necessary to identify the mechanism of their action and characterize their interaction with eukaryotic cells/organisms in more detail. Here, we show that at their bactericidal concentrations LPPOs localize to the plasmatic membrane in bacteria but not in eukaryotes. In an in vitro system we demonstrate that LPPOs create pores in the membrane. This provides an explanation of their action in vivo where they cause serious damage of the cellular membrane, efflux of the cytosol, and cell disintegration. Further, we show that (i) LPPOs are not genotoxic as determined by the Ames test, (ii) do not cross a monolayer of Caco-2 cells, suggesting they are unable of transepithelial transport, (iii) are well tolerated by living mice when administered orally but not peritoneally, and (iv) are stable at low pH, indicating they could survive the acidic environment in the stomach. Finally, using one of the most potent LPPOs, we attempted and failed to select resistant strains against this compound while we were able to readily select resistant strains against a known antibiotic, rifampicin. In summary, LPPOs represent a new class of compounds with a potential for development as antibacterial agents for topical applications and perhaps also for treatment of gastrointestinal infections.
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- 2015
- Full Text
- View/download PDF
4. The mycobacterial guaB1 gene encodes a guanosine 5'-monophosphate reductase with a cystathionine-β-synthase domain
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Zdeněk Knejzlík, Michal Doležal, Klára Herkommerová, Kamila Clarova, Martin Klíma, Matteo Dedola, Eva Zborníková, Dominik Rejman, and Iva Pichová
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Adenosine Triphosphate ,Cystathionine ,IMP Dehydrogenase ,GMP Reductase ,Inosine Monophosphate ,Guanosine Monophosphate ,Cystathionine beta-Synthase ,Cell Biology ,Guanosine Triphosphate ,Mycobacterium tuberculosis ,Molecular Biology ,Biochemistry ,Inosine - Abstract
Mycobacteria express enzymes from both the de novo and purine-salvage pathways. However, the regulation of these processes and the roles of individual metabolic enzymes have not been sufficiently detailed. Both Mycobacterium tuberculosis (Mtb) and Mycobacterium smegmatis (Msm) possess three guaB genes, but information is only available on guaB2, which encodes an essential inosine 5'-monophosphate dehydrogenase (IMPDH) involved in de novo purine biosynthesis. This study shows that guaB1, annotated in databases as a putative IMPDH, encodes a guanosine 5'-monophosphate reductase (GMPR), which recycles guanosine monophosphate to inosine monophosphate within the purine-salvage pathway and contains a cystathionine-β-synthase domain (CBS), which is essential for enzyme activity. GMPR activity is allosterically regulated by the ATP/GTP ratio in a pH-dependent manner. Bioinformatic analysis has indicated the presence of GMPRs containing CBS domains across the entire Actinobacteria phylum.
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- 2022
5. Author response for 'The mycobacterial guaB1 gene encodes a guanosine 5´‐monophosphate reductase with a cystathionine‐β‐synthase domain'
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null Zdeněk Knejzlík, null Michal Doležal, null Klára Herkommerová, null Kamila Clarova, null Martin Klíma, null Matteo Dedola, null Eva Zborníková, null Dominik Rejman, and null Iva Pichová
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- 2022
6. Evaluation of Second-Generation Lipophosphonoxins as Antimicrobial Additives in Bone Cement
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Zdeněk Hrdlička, Eva Zborníková, Milan Kolář, Ondřej Pačes, Dominik Rejman, Dragana Vítovská, Libor Krásný, Jitka Ulrichová, Duy Dinh Do Pham, Drahomír Čadek, Hana Šanderová, Viktor Mojr, Kateřina Bogdanová, J. Gallo, Adéla Galandáková, and Renata Večeřová
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medicine.medical_specialty ,Implant surface ,business.industry ,General Chemical Engineering ,technology, industry, and agriculture ,Dentistry ,General Chemistry ,equipment and supplies ,Antimicrobial ,Bone cement ,Article ,Chemistry ,Orthopedic surgery ,Medicine ,business ,QD1-999 - Abstract
Successful surgeries involving orthopedic implants depend on the avoidance of biofilm development on the implant surface during the early postoperative period. Here, we investigate the potential of novel antibacterial compounds-second-generation lipophosphonoxins (LPPOs II)-as additives to surgical bone cements. We demonstrate (i) excellent thermostability of LPPOs II, which is essential to withstand elevated temperatures during exothermic cement polymerization; (ii) unchanged tensile strength and elongation at the break properties of the composite cements containing LPPOs II compared to cements without additives; (iii) convenient elution kinetics on the order of days; and (iv) the strong antibiofilm activity of the LPPO II-loaded cements even against bacteria resistant to the medicinally utilized antibiotic, gentamicin. Thus, LPPOs II display promising potential as antimicrobial additives to surgical bone cements.
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- 2020
7. The mycobacterial guaB1 gene encodes a guanosine 5’-monophosphate reductase with a cystathione-β-synthase domain
- Author
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M. Klima, Iva Pichová, K. Clarova, Eva Zborníková, M. Dolezal, Klára Herkommerová, Zdeněk Knejzlík, Dominik Rejman, and M. Dedola
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chemistry.chemical_classification ,Inosine monophosphate ,biology ,Mycobacterium smegmatis ,Guanosine ,biology.organism_classification ,chemistry.chemical_compound ,chemistry ,Biochemistry ,IMP dehydrogenase ,Guanosine monophosphate ,Nucleotide ,Purine metabolism ,Nucleotide salvage - Abstract
Purine metabolism plays a pivotal role in bacterial life cycle, however, regulation of the de novo and purine salvage pathways have not been extensively detailed in mycobacteria. By gene knockout, biochemical and structural analyses, we identified Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb) guaB1 gene product as a novel type of guanosine 5’-monophosphate reductase (GMPR), which recycles guanosine monophosphate to inosine monophosphate within the purine salvage pathway and contains cystathione β-synthase (CBS) domains with atypical orientation in the octamer. CBS domains share a much larger interacting area with a conserved catalytic domain in comparison with the only known CBS containing protozoan GMPR and closely related inosine monophosphate dehydrogenase structures. Our results revealed essential effect of pH on allosteric regulation of Msm GMPR activity and oligomerization with adenine and guanosine nucleotides binding to CBS domains.Bioinformatic analysis indicated the presence of GMPRs containing CBS domains across the entire Actinobacteria phylum.
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- 2021
8. Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics
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Dominik Rejman, Ian M. Brereton, Lieve Naesens, Luke W. Guddat, Dana Hocková, Tristan I. Croll, Dianne T. Keough, Eva Zborníková, Gregory K. Pierens, Radek Pohl, Marina Chavchich, Michael D. Edstein, and Geoff W. Birrell
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Models, Molecular ,0301 basic medicine ,Hypoxanthine Phosphoribosyltransferase ,Protein Conformation ,Plasmodium vivax ,Chemistry Techniques, Synthetic ,Pharmacology ,Crystallography, X-Ray ,Biochemistry ,Pyrrolidine ,Antimalarials ,03 medical and health sciences ,chemistry.chemical_compound ,Catalytic Domain ,parasitic diseases ,Humans ,Transferase ,Pentosyltransferases ,chemistry.chemical_classification ,Diphosphonates ,biology ,Drug discovery ,Escherichia coli Proteins ,Plasmodium falciparum ,General Medicine ,Xanthine ,biology.organism_classification ,030104 developmental biology ,Enzyme ,chemistry ,Hypoxanthine-guanine phosphoribosyltransferase ,Drug Design ,Molecular Medicine - Abstract
Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT that has Ki values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 A resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide ...
- Published
- 2017
9. Lipophosphonoxins II: Design, Synthesis, and Properties of Novel Broad Spectrum Antibacterial Agents
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Marcel Ehn, Radek Pohl, Jiří Pospíšil, Gabriela Seydlová, Tomáš Křížek, David Sedlák, Dominik Rejman, Radovan Fišer, Libor Krásný, Oldřich Benada, Milan Kolář, Renata Večeřová, Dragana Vítovská, Petra Sudzinová, Eva Zborníková, Ondřej Šimák, Hana Šanderová, Kateřina Bogdanová, Natalya Panova, and Petr Bartůněk
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Male ,0301 basic medicine ,Cell Survival ,medicine.drug_class ,Lipid Bilayers ,030106 microbiology ,Antibiotics ,Apoptosis ,Microbial Sensitivity Tests ,Gram-Positive Bacteria ,Cell Line ,Microbiology ,Structure-Activity Relationship ,03 medical and health sciences ,Broad spectrum ,Cell Line, Tumor ,Drug Resistance, Multiple, Bacterial ,Gram-Negative Bacteria ,Drug Discovery ,medicine ,Animals ,Humans ,Mode of action ,Phospholipids ,Mice, Inbred ICR ,biology ,Resistance development ,Chemistry ,Cell Membrane ,Stereoisomerism ,Skin Irritancy Tests ,biology.organism_classification ,Anti-Bacterial Agents ,Plasmatic membrane ,Membrane ,Design synthesis ,Drug Design ,Pyrazoles ,Molecular Medicine ,Rabbits ,Uridine Monophosphate ,Bacteria - Abstract
The increase in the number of bacterial strains resistant to known antibiotics is alarming. In this study we report the synthesis of novel compounds termed Lipophosphonoxins II (LPPO II). We show that LPPO II display excellent activities against Gram-positive and -negative bacteria, including pathogens and multiresistant strains. We describe their mechanism of action-plasmatic membrane pore-forming activity selective for bacteria. Importantly, LPPO II neither damage nor cross the eukaryotic plasmatic membrane at their bactericidal concentrations. Further, we demonstrate LPPO II have low propensity for resistance development, likely due to their rapid membrane-targeting mode of action. Finally, we reveal that LPPO II are not toxic to either eukaryotic cells or model animals when administered orally or topically. Collectively, these results suggest that LPPO II are highly promising compounds for development into pharmaceuticals.
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- 2017
10. Analysis of Nucleotide Pools in Bacteria Using HPLC-MS in HILIC Mode
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Dominik Rejman, Vasili Hauryliuk, Libor Krásný, Zdeněk Knejzlík, and Eva Zborníková
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Analyte ,02 engineering and technology ,01 natural sciences ,High-performance liquid chromatography ,Mass Spectrometry ,Bacterial cell structure ,Analytical Chemistry ,law.invention ,Limit of Detection ,law ,Molecule ,Nucleotide ,Chromatography, High Pressure Liquid ,Filtration ,chemistry.chemical_classification ,Chromatography ,Escherichia coli K12 ,biology ,Nucleotides ,Chemistry ,Hydrophilic interaction chromatography ,010401 analytical chemistry ,Extraction (chemistry) ,Hydrogen-Ion Concentration ,021001 nanoscience & nanotechnology ,biology.organism_classification ,0104 chemical sciences ,Solvents ,0210 nano-technology ,Intracellular ,Bacteria - Abstract
Nucleotides, nucleosides and their derivatives are present in cells at varying concentrations that rapidly change with the nutritional, and energetic status of the cell. Knowledge of the concentration dynamics of these molecules is instrumental for understanding their regulatory effects. Determination of these concentrations is challenging due to the inherent instability of these molecules and, despite many decades of research, the reported values differ widely. Here, we present a comprehensive and easy-to-use approach to determine intracellular concentrations of >25 target molecular species. The approach uses rapid filtration and cold acidic extraction followed by high performance liquid chromatography (HPLC) in the hydrophilic interaction liquid chromatography (HILIC) mode using zwitterionic columns coupled with UV and MS detectors. The method reliably detects and quantifies all the analytes expected to be observed in the bacterial cell and paves the way for future studies correlating their concentrations with biological effects.
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- 2019
11. Adenosine triphosphate analogs can efficiently inhibit the Zika virus RNA-dependent RNA polymerase
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Eva Zborníková, Milan Dejmek, Miroslav Smola, Jaroslav Kozák, Hubert Hřebabecký, Michal Šála, Daniel Ruzek, Evzen Boura, Radim Nencka, and Kamil Hercik
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0301 basic medicine ,Ribonucleotide ,Molecular Conformation ,RNA-dependent RNA polymerase ,Antiviral Agents ,law.invention ,Zika virus ,03 medical and health sciences ,chemistry.chemical_compound ,Adenosine Triphosphate ,law ,Virology ,RNA polymerase ,Drug Discovery ,Humans ,Enzyme Inhibitors ,Pharmacology ,biology ,Drug discovery ,Nucleosides ,Zika Virus ,Carbohydrate ,RNA-Dependent RNA Polymerase ,biology.organism_classification ,Molecular biology ,030104 developmental biology ,chemistry ,Biochemistry ,Recombinant DNA ,Adenosine triphosphate - Abstract
We describe the expression and purification of an active recombinant Zika virus RNA-dependent RNA polymerase (RdRp). Next, we present the development and optimization of an in vitro assay to measure its activity. We then applied the assay to selected triphosphate analogs and discovered that 2'-C-methylated nucleosides exhibit strong inhibitory activity. Surprisingly, also carbocyclic derivatives with the carbohydrate locked in a North-like conformation as well as a ribonucleotide with a South conformation exhibited strong activity. Our results suggest that the traditional 2'-C-methylated nucleosides pursued in the race for anti-HCV treatment can be superseded by brand new scaffolds in the case of the Zika virus.
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- 2017
12. Could 5′-N and S ProTide analogues work as prodrugs of antiviral agents?
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Milan Dejmek, Markéta Šmídková, Luděk Eyer, Radim Nencka, Daniel Růžek, Hubert Hřebabecký, Eliška Procházková, Eva Zborníková, Eva Tloušťová, and Michal Šála
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Adenosine ,Magnetic Resonance Spectroscopy ,Nitrogen ,Hepatitis C virus ,Clinical Biochemistry ,Pharmaceutical Science ,Protide ,Hepacivirus ,medicine.disease_cause ,Antiviral Agents ,01 natural sciences ,Biochemistry ,Modified nucleosides ,Dengue fever ,Flaviviridae ,Drug Discovery ,medicine ,Humans ,Prodrugs ,Molecular Biology ,biology ,Nucleotides ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Antiviral therapy ,Zika Virus ,Dengue Virus ,Prodrug ,medicine.disease ,biology.organism_classification ,Virology ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Molecular Medicine ,Nucleoside ,Sulfur - Abstract
The nucleoside/nucleotide derived antiviral agents have been the most important components of antiviral therapy used in clinics. Recently, the focus of the medicinal chemists within this exciting research field has been affected mainly by the lack of effective therapies for the Hepatitis C virus (HCV) infection and several other "neglected" diseases caused by viruses such as Zika or Dengue. 2'-Methyl modified nucleosides and their monophosphate prodrugs (ProTides) have revolutionized the therapies for HCV in the last few years and, according to the latest research efforts, have also brought a promise for treatment of diseases caused by other members of Flaviviridae family. Here, we report on the design and synthesis of 5'-N and S modified ProTides derived from 2'-methyladenosine. We studied potential applicability of these derivatives as prodrugs of this archetypal antiviral compound.
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- 2020
13. A new class of phosphanucleosides containing a 3-hydroxy-1-hydroxymethylphospholane 1-oxide ring
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Eva Zborníková, Miloš Buděšínský, Ondřej Páv, and Ivan Rosenberg
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Nucleoside analogue ,Chemistry ,Stereochemistry ,Organic Chemistry ,Oxide ,Epoxide ,Biological activity ,Ring (chemistry) ,Biochemistry ,Nucleobase ,chemistry.chemical_compound ,Drug Discovery ,medicine ,medicine.drug - Abstract
Novel phosphanucleosides containing a 3-hydroxy-1-hydroxymethylphospholane 1-oxide ring were synthesized as compounds with potential biological activity. A double Arbuzov reaction was employed to prepare a phospholene precursor, which was then converted into an epoxide and subsequently into racemic phosphanucleoside via nucleobase construction.
- Published
- 2013
14. Activation of human RNase L by 2′- and 5′-O-methylphosphonate-modified oligoadenylates
- Author
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Ondřej Páv, Natalya Panova, Eva Zborníková, Ivan Rosenberg, and Jan Snášel
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Time Factors ,RNase P ,Stereochemistry ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Organophosphonates ,Pharmaceutical Science ,Cleavage (embryo) ,Biochemistry ,RNase PH ,Mice ,chemistry.chemical_compound ,Tetramer ,Endoribonucleases ,Drug Discovery ,Fluorescence Resonance Energy Transfer ,Animals ,Humans ,Molecular Biology ,Oligoribonucleotides ,Cell-Free System ,Adenine Nucleotides ,Organic Chemistry ,Phosphate ,Phosphonate ,Förster resonance energy transfer ,Monomer ,Models, Chemical ,chemistry ,Drug Design ,Molecular Medicine ,Dimerization - Abstract
To determine the influence of internucleotide linkage and sugar ring conformation, and the role of 5′-terminal phosphate, on the activation of human RNase L, a series of 2′- and 5′-O-methylphosphonate-modified tetramers were synthesized from appropriate monomeric units and evaluated for their ability to activate human RNase L. Tetramers pAAApcX modified by ribo, arabino or xylo 5′-phosphonate unit pcX activated RNase L with efficiency comparable to that of natural activator. Moreover, incorporation of phosphonate linkages ensured the stability against cleavage by nucleases. The substitution of 5′-terminal phosphate for 5′-terminal phosphonate in tetramer pcXAAA afforded tetramers with excellent activation efficiency and with complete stability against cleavage by phosphomonoesterases.
- Published
- 2012
15. Lipophosphonoxins: New Modular Molecular Structures with Significant Antibacterial Properties
- Author
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Petr Bartůněk, Kateřina Bogdanová, Otakar Nyc, Radek Pohl, Milan Kolář, Eva Zborníková, Soňa Kovačková, Antonio R. Pombinho, Alžbeta Rabatinová, Libor Krásný, Hana Šanderová, Dominik Rejman, and Tomáš Látal
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Cell Survival ,Stereochemistry ,Organophosphonates ,Iminosugar ,Apoptosis ,Stereoisomerism ,Microbial Sensitivity Tests ,Gram-Positive Bacteria ,Structure-Activity Relationship ,chemistry.chemical_compound ,Minimum inhibitory concentration ,Drug Resistance, Multiple, Bacterial ,Drug Discovery ,Humans ,Structure–activity relationship ,Cells, Cultured ,Alkyl ,Erythroid Precursor Cells ,chemistry.chemical_classification ,Nucleosides ,Fetal Blood ,Phosphonate ,Combinatorial chemistry ,Anti-Bacterial Agents ,chemistry ,Molecular Medicine ,Hydrophobic and Hydrophilic Interactions ,Nucleoside ,Linker - Abstract
Novel compounds termed lipophosphonoxins were prepared using a simple and efficient synthetic approach. The general structure of lipophosphonoxins consists of four modules: (i) a nucleoside module, (ii) an iminosugar module, (iii) a hydrophobic module (lipophilic alkyl chain), and (iv) a phosphonate linker module that holds together modules i-iii. Lipophosphonoxins displayed significant antibacterial properties against a panel of Gram-positive species, including multiresistant strains. The minimum inhibitory concentration (MIC) values of the best inhibitors were in the 1-12 μg/mL range, while their cytotoxic concentrations against human cell lines were significantly above this range. The modular nature of this artificial scaffold offers a large number of possibilities for further modifications/exploitation of these compounds.
- Published
- 2011
16. Straightforward Synthesis of Purine 4'-Alkoxy-2'-deoxynucleosides: First Report of Mixed Purine-Pyrimidine 4'-Alkoxyoligodeoxynucleotides as New RNA Mimics
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Ivana Dvořáková, Magdalena Petrová, Miloš Buděšínský, Eva Zborníková, Ondřej Šimák, Ondřej Pačes, Šárka Rosenbergová, Pavel Novák, Radek Liboska, Ondřej Páv, and Ivan Rosenberg
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Purine ,Pyrimidine ,Stereochemistry ,Molecular Conformation ,Succinimides ,Biochemistry ,chemistry.chemical_compound ,Organic chemistry ,Physical and Theoretical Chemistry ,Phosphoramidite ,Nuclease ,biology ,Molecular Structure ,Chemistry ,Oligonucleotide ,Organic Chemistry ,RNA ,Nucleic Acid Hybridization ,Oligonucleotides, Antisense ,Oligodeoxyribonucleotides ,Purines ,biology.protein ,Alkoxy group ,Nucleic Acid Conformation ,Nucleoside - Abstract
Purine and pyrimidine 4′-alkoxy-2′-deoxynucleosides were efficiently prepared from nucleoside 4′-5′-enol acetates in three steps by N-iodosuccinimide promoted alkoxylation, hydrolysis, and reduction followed by conversion to phosphoramidite monomers for the solid-phase synthesis of the oligonucleotides. Fully modified 4′-alkoxyoligodeoxynucleotides, which are characterized by a prevalent N-type (RNA-like) conformation, exhibited superior chemical and nuclease resistance as well as excellent hybridization properties with a strong tendency for RNA-selective hybridization, suggesting a potential application of 4′-alkoxy-oligodeoxynucleotides in antisense technologies.
- Published
- 2015
17. ChemInform Abstract: A New Class of Phosphanucleosides Containing a 3-Hydroxy-1-hydroxymethylphospholane 1-Oxide Ring
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Eva Zborníková, Ondrej Pav, Ivan Rosenberg, and Milos Budesinsky
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chemistry.chemical_compound ,Chemistry ,Nucleic acid ,Oxide ,Organic chemistry ,General Medicine ,Ring (chemistry) - Published
- 2014
18. Activation of human RNase L by 5’-C-phosphonate-modified oligoadenylates
- Author
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Pavel Novák, Eva Zborníková, Ivan Rosenberg, Miloš Buděšínský, Magdalena Petrová, and Natalia Panova
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chemistry.chemical_compound ,chemistry ,Stereochemistry ,RNase P ,Phosphonate - Published
- 2014
19. Phosphanucleosides containing 1-hydroxymethylphospholane 1-oxide ring
- Author
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Ondřej Páv, Ivan Rosenberg, Miloš Buděšínský, and Eva Zborníková
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chemistry.chemical_compound ,chemistry ,Polymer chemistry ,Oxide ,Ring (chemistry) - Published
- 2014
20. Sulfur-containing phosphonate monomers for oligonucleotide synthesis
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Ivan Rosenberg, Eva Zborníková, Pavel Novák, Miloš Buděšínský, and Ondřej Kostov
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chemistry.chemical_compound ,Monomer ,chemistry ,Oligonucleotide synthesis ,Sulfur containing ,Combinatorial chemistry ,Phosphonate - Published
- 2014
21. Insights into the mechanism of action of bactericidal lipophosphonoxins
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Gabriela Seydlová, Natalia Panova, Eva Zborníková, Ondřej Šimák, Milan Kolář, Libor Krásný, Dominik Rejman, and Tomáš Látal
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Mechanism of action ,Chemistry ,medicine ,Biophysics ,medicine.symptom - Published
- 2014
22. Synthesis of alkylcarbonate analogs of O-acetyl-ADP-ribose
- Author
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Milan Dejmek, Radek Pohl, Marie Pribylova, Tomas Vanek, Marie E. Migaud, Eva Zborníková, Radim Nencka, Marcela Dvorakova, and Anna Brezinova
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biology ,Dose-Response Relationship, Drug ,Stereochemistry ,Organic Chemistry ,Carbonates ,Molecular Conformation ,O-Acetyl-ADP-Ribose ,environment and public health ,Biochemistry ,enzymes and coenzymes (carbohydrates) ,chemistry.chemical_compound ,Structure-Activity Relationship ,chemistry ,Sirtuin 1 ,Ribose ,Sirtuin ,biology.protein ,Phosphorylation ,Humans ,Physical and Theoretical Chemistry ,Enzyme Inhibitors - Abstract
The non-hydrolyzable alkylcarbonate analogs of O-acetyl-ADP-ribose have been synthesized from the phosphorylated ribose derivatives after coupling with AMP morpholidate promoted by mechanical grinding. The analogs were assessed for their ability to inhibit the human sirtuin homolog SIRT1.
- Published
- 2013
23. ChemInform Abstract: One-Pot Build-Up Procedure for the Synthesis of Variously Substituted Purine Derivatives
- Author
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Michal Šála, Eva Zborníková, Sona Kovackova, Martin Dracinsky, Radim Nencka, Milan Dejmek, and Hubert Hrebabecky
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chemistry.chemical_compound ,Pyrimidine ,Chemistry ,fungi ,food and beverages ,Purine derivative ,Single step ,General Medicine ,Combinatorial chemistry - Abstract
A convenient and simplified route to the title purine derivatives (III) can be carried out in a single step by using commercially available pyrimidine precursors.
- Published
- 2012
24. Insights into the Mechanism of Action of Bactericidal Lipophosphonoxins
- Author
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Libor Krásný, Radovan Fišer, Dragana Vítovská, Hana Šanderová, Romana Hadravová, Renata Večeřová, Milan Kolář, Dominik Rejman, Kateřina Bogdanová, Tomáš Látal, Ivan Barvík, Michaela Šiková, Eva Zborníková, Ondřej Šimák, Natalya Panova, Petra Lovecká, Radek Pohl, and Gabriela Seydlová
- Subjects
Male ,Cell Membrane Permeability ,medicine.drug_class ,Antibiotics ,Cell ,lcsh:Medicine ,Biological Transport, Active ,Microbial Sensitivity Tests ,Biology ,Gram-Positive Bacteria ,Streptococcus agalactiae ,Microbiology ,Ames test ,Mice ,Drug Stability ,Microscopy, Electron, Transmission ,In vivo ,Drug Discovery ,Enterococcus faecalis ,medicine ,Animals ,Humans ,lcsh:Science ,Mice, Inbred ICR ,Multidisciplinary ,Molecular Structure ,lcsh:R ,Cell Membrane ,Pyrimidine Nucleosides ,biology.organism_classification ,Anti-Bacterial Agents ,Cytosol ,medicine.anatomical_structure ,Mechanism of action ,Biochemistry ,lcsh:Q ,Female ,Efflux ,Caco-2 Cells ,medicine.symptom ,Bacteria ,Bacillus subtilis ,Protein Binding ,Research Article - Abstract
The advantages offered by established antibiotics in the treatment of infectious diseases are endangered due to the increase in the number of antibiotic-resistant bacterial strains. This leads to a need for new antibacterial compounds. Recently, we discovered a series of compounds termed lipophosphonoxins (LPPOs) that exhibit selective cytotoxicity towards Gram-positive bacteria that include pathogens and resistant strains. For further development of these compounds, it was necessary to identify the mechanism of their action and characterize their interaction with eukaryotic cells/organisms in more detail. Here, we show that at their bactericidal concentrations LPPOs localize to the plasmatic membrane in bacteria but not in eukaryotes. In an in vitro system we demonstrate that LPPOs create pores in the membrane. This provides an explanation of their action in vivo where they cause serious damage of the cellular membrane, efflux of the cytosol, and cell disintegration. Further, we show that (i) LPPOs are not genotoxic as determined by the Ames test, (ii) do not cross a monolayer of Caco-2 cells, suggesting they are unable of transepithelial transport, (iii) are well tolerated by living mice when administered orally but not peritoneally, and (iv) are stable at low pH, indicating they could survive the acidic environment in the stomach. Finally, using one of the most potent LPPOs, we attempted and failed to select resistant strains against this compound while we were able to readily select resistant strains against a known antibiotic, rifampicin. In summary, LPPOs represent a new class of compounds with a potential for development as antibacterial agents for topical applications and perhaps also for treatment of gastrointestinal infections.
- Published
- 2015
25. One-pot build-up procedure for the synthesis of variously substituted purine derivatives
- Author
-
Radim Nencka, Milan Dejmek, Michal Šála, Eva Zborníková, Soňa Kovačková, Martin Dračínský, and Hubert Hřebabecký
- Subjects
chemistry.chemical_classification ,chemistry.chemical_compound ,Nucleophile ,Chemistry ,General Chemical Engineering ,Reagent ,Aryl ,Chlorine atom ,Purine derivative ,Organic chemistry ,Amine gas treating ,General Chemistry ,Alkyl - Abstract
In this article, we report a one-pot build-up procedure leading to 6-chloro- or 2-amino-6-chloropurines bearing various alkyl or aryl substituents in position N-9. This reaction is simple, fast and effective with up to 96% yields depending on the starting amine. This reaction may be easily combined with further nucleophilic displacement of the C-6 chlorine atom using various reagents, making this procedure very attractive in the field of medicinal chemistry pertaining to compounds based on a purine scaffold.
- Published
- 2012
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