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Berlin Brandenburg

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  • 1
    Language: English
    In: Analytical Biochemistry, 2001, Vol.294(2), pp.194-195
    Keywords: Chemistry ; Anatomy & Physiology
    ISSN: 0003-2697
    E-ISSN: 1096-0309
    Source: ScienceDirect Journals (Elsevier)
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  • 2
    Language: English
    In: Future microbiology, 2014, Vol.9(10), pp.1113-6
    Description: [...]avibactam, a non-β-lactam β-lactamase inhibitor, delivered in combination with ceftazadime was the only novel anti-GNB in clinical trials. [...]many major pharmaceutical companies have exited antimicrobial R&D. In order to address the dearth of antibiotic development, in 2012 the Generating Antibiotic...
    Keywords: Acinetobacter Baumannii ; Gram-Negative Bacilli ; Antibiotic Target ; Bacterial Drug Target ; Essential Genes ; Multidrug Resistant ; Drug Resistance, Multiple, Bacterial ; Anti-Infective Agents -- Isolation & Purification ; Drug Discovery -- Methods ; Gram-Negative Bacteria -- Drug Effects
    ISSN: 17460913
    E-ISSN: 1746-0921
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  • 3
    Language: English
    In: Virus Research, March 2013, Vol.172(1-2), pp.75-80
    Description: Influenza A virus is an important human pathogen accounting for widespread morbidity and mortality, with new strains emerging from animal reservoirs possessing the potential to cause pandemics. The influenza A RNA-dependent RNA polymerase complex consists of three subunits (PA, PB1, and PB2) and catalyzes viral RNA replication and transcription activities in the nuclei of infected host cells. The PB2 subunit has been implicated in pathogenicity and host adaptation. This includes the inhibition of type I interferon induction through interaction with the host's mitochondrial antiviral signaling protein (MAVS), an adaptor molecule of RIG-I-like helicases. This study reports the identification of the cognate PB2 and MAVS interaction domains necessary for complex formation. Specifically, MAVS residues 1–150, containing both the CARD domain and the N-terminal portion of the proline rich-region, and PB2 residues 1–37 are essential for PB2–MAVS virus–host protein–protein complex formation. The three α-helices constituting PB2 (1–37) were tested to determine their relative influence in complex formation, and Helix3 was observed to promote the primary interaction with MAVS. The PB2 MAVS-binding domain unexpectedly coincided with its PB1-binding domain, indicating an important dual functionality for this region of PB2. Analysis of these interaction domains suggests both virus and host properties that may contribute to host tropism. Additionally, the results of this study suggest a new strategy to develop influenza A therapeutics by simultaneously blocking PB2–MAVS and PB2–PB1 protein–protein interactions and their resulting activities.
    Keywords: Influenza A Virus ; Polymerase Subunit Pb2 ; Polymerase Subunit Pb1 ; Mitochondrial Antiviral Signaling Protein (Mavs) ; Protein–Protein Interaction (Ppi) ; Host Tropism ; Biology
    ISSN: 0168-1702
    E-ISSN: 1872-7492
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 13 February 2001, Vol.98(4), pp.1459-1464
    Description: The yeast nonchromosomal gene [URE3] is due to a prion form of the nitrogen regulatory protein Ure2p. It is a negative regulator of nitrogen catabolism and acts by inhibiting the transcription factor Gln3p. Ure2p residues 1-80 are necessary for prion generation and propagation. The C-terminal fragment retains nitrogen regulatory activity, albeit somewhat less efficiently than the full-length protein, and it also lowers the frequency of prion generation. The crystal structure of this C-terminal fragment, Ure2p(97-354), at 2.3 Å resolution is described here. It adopts the same fold as the glutathione S-transferase superfamily, consistent with their sequence similarity. However, Ure2p(97-354) lacks a properly positioned catalytic residue that is required for S-transferase activity. Residues within this regulatory fragment that have been indicated by mutational studies to influence prion generation have been mapped onto the three-dimensional structure, and possible implications for prion activity are discussed.
    Keywords: Physical sciences -- Chemistry -- Chemical compounds ; Physical sciences -- Chemistry -- Chemical elements ; Physical sciences -- Chemistry -- Chemical compounds ; Physical sciences -- Chemistry -- Chemical compounds ; Physical sciences -- Physics -- Condensed matter physics ; Physical sciences -- Physics -- Microphysics ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Mycology ; Political science -- Government -- Governance ; Physical sciences -- Chemistry -- Chemical mixtures
    ISSN: 00278424
    E-ISSN: 10916490
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  • 5
    In: Infection and Immunity, 2010, Vol. 78(9), p.3993
    Description: Acinetobacter baumannii is a pathogen of increasing medical importance with a propensity to be multidrug resistant, thereby making treatment challenging. Little is known of virulence traits in A. baumannii. To identify virulence factors and potential drug targets, random transposon (Tn) mutants derived from the A. baumannii strain AB307-0294 were screened to identify genes essential for growth in human ascites fluid in vitro, an inflammatory exudative fluid. These studies led to the identification of two genes that were predicted to be required for capsule polymerization and assembly. The first, ptk, encodes a putative protein tyrosine kinase (PTK), and the second, epsA, encodes a putative polysaccharide export outer membrane protein (EpsA). Monoclonal antibodies used in flow cytometric and Western analyses confirmed that these genes are required for a capsule-positive phenotype. A capsule-positive phenotype significantly optimized growth in human ascites fluid, survival in human serum, and survival in a rat soft tissue infection model. Importantly, the clearance of the capsule-minus mutants AB307.30 (ptk mutant, capsule minus) and AB307.45 (epsA mutant, capsule minus) was complete and durable. These data demonstrated that the K1 capsule from AB307-0294 was an important protectin. Further, these data suggested that conserved proteins, which contribute to the capsule-positive phenotype, are potential antivirulence drug targets. Therefore, the results from this study have important biologic and translational implications and, to the best of our knowledge, are the first to address the role of capsule in the pathogenesis of A. baumannii infection.
    Keywords: Translation ; Outer Membrane Proteins ; Data Processing ; Polymerization ; Virulence Factors ; Monoclonal Antibodies ; Animal Models ; Survival ; Medical Importance ; Pathogens ; Infection ; Inflammation ; Flow Cytometry ; Transposons ; Ascites ; Protein-Tyrosine Kinase ; Multidrug Resistance ; Soft Tissues ; Capsular Polysaccharides ; Drugs ; Acinetobacter Baumannii ; Microorganisms & Parasites ; Immunology;
    ISSN: 0019-9567
    ISSN: 00199567
    E-ISSN: 10985522
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  • 6
    Language: English
    In: mSphere, 2016, Vol.1(6)
    Description: The use of amphotericin B (AmB) in conjunction with 5-fluorocytosine (5-FC) is known to be the optimal therapy for treating cryptococcosis, but the mechanism by which 5-FC synergizes with AmB is unknown. In this study, we generated a Δ mutant lacking dihydroorotate dehydrogenase (DHODH), which demonstrated temperature-sensitive growth due to a defect in cell integrity and sensitivity to cell wall-damaging agents. In addition, sensitivity to AmB was greatly increased. Inclusion of uracil or uridine in the medium did not suppress the cell wall or AmB phenotype, whereas complementation with the wild-type gene complemented the mutant phenotype. As a measure of membrane accessibility, we assayed the rate of association of the lipid-binding dye 3,3'-dihexyloxacarbocyanine iodide (DiOC) and saw more rapid association in the Δ mutant. We likewise saw an increased rate of DiOC association in other AmB-sensitive mutants, including a spontaneous mutant made by 5-fluoroorotic acid (5-FOA) selection and a Δ mutant defective in cell integrity signaling. Similar results were also obtained by using a specific plasma membrane-binding CellMask live stain, with cell integrity mutants that exhibited increased and faster association of the dye with the membrane. Chitin synthase mutants (Δ and Δ) that lack any reported cell wall defects, in turn, demonstrate neither any increased susceptibility to AmB nor a greater accessibility to either of the dyes. Finally, perturbation of the cell wall of the wild type by treatment with the β-1,6-glucan synthase inhibitor caspofungin was synergistic with AmB . Synergy between AmB and nucleotide biosynthetic pathways has been documented, but the mechanism of this interaction has not been delineated. Results from this study suggest a correlation between uridine nucleotide biosynthesis and cell integrity likely mediated through the pool of nucleotide-sugar conjugates, which are precursor molecules for both capsule and cell wall of . Thus, we propose a mechanism by which structural defects in the cell wall resulting from perturbation of pyrimidine biosynthesis allow faster and increased penetration of AmB molecules into the cell membrane. Overall, our work demonstrates that impairment of pyrimidine biosynthesis in could be a potential target for antifungal therapy, either alone or in combination with AmB.
    Keywords: Amphotericin B ; Cell Wall Integrity ; Pyrimidine Biosynthesis
    ISSN: 2379-5042
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 7
    Language: English
    In: mSphere, 01 November 2016, Vol.1(6), p.e00191-16
    Description: Synergy between AmB and nucleotide biosynthetic pathways has been documented, but the mechanism of this interaction has not been delineated. Results from this study suggest a correlation between uridine nucleotide biosynthesis and cell integrity likely mediated through the pool of nucleotide-sugar conjugates, which are precursor molecules for both capsule and cell wall of C. neoformans . Thus, we propose a mechanism by which structural defects in the cell wall resulting from perturbation of pyrimidine biosynthesis allow faster and increased penetration of AmB molecules into the cell membrane. Overall, our work demonstrates that impairment of pyrimidine biosynthesis in C. neoformans could be a potential target for antifungal therapy, either alone or in combination with AmB. ABSTRACT The use of amphotericin B (AmB) in conjunction with 5-fluorocytosine (5-FC) is known to be the optimal therapy for treating cryptococcosis, but the mechanism by which 5-FC synergizes with AmB is unknown. In this study, we generated a Cryptococcus neoformans ura1 Δ mutant lacking dihydroorotate dehydrogenase (DHODH), which demonstrated temperature-sensitive growth due to a defect in cell integrity and sensitivity to cell wall-damaging agents. In addition, sensitivity to AmB was greatly increased. Inclusion of uracil or uridine in the medium did not suppress the cell wall or AmB phenotype, whereas complementation with the wild-type URA1 gene complemented the mutant phenotype. As a measure of membrane accessibility, we assayed the rate of association of the lipid-binding dye 3,3′-dihexyloxacarbocyanine iodide (DiOC 6 ) and saw more rapid association in the ura1 Δ mutant. We likewise saw an increased rate of DiOC 6 association in other AmB-sensitive mutants, including a ura − spontaneous URA5 mutant made by 5-fluoroorotic acid (5-FOA) selection and a bck1 Δ mutant defective in cell integrity signaling. Similar results were also obtained by using a specific plasma membrane-binding CellMask live stain, with cell integrity mutants that exhibited increased and faster association of the dye with the membrane. Chitin synthase mutants ( chs5 Δ and chs6 Δ) that lack any reported cell wall defects, in turn, demonstrate neither any increased susceptibility to AmB nor a greater accessibility to either of the dyes. Finally, perturbation of the cell wall of the wild type by treatment with the β-1,6-glucan synthase inhibitor caspofungin was synergistic with AmB in vitro . IMPORTANCE Synergy between AmB and nucleotide biosynthetic pathways has been documented, but the mechanism of this interaction has not been delineated. Results from this study suggest a correlation between uridine nucleotide biosynthesis and cell integrity likely mediated through the pool of nucleotide-sugar conjugates, which are precursor molecules for both capsule and cell wall of C. neoformans . Thus, we propose a mechanism by which structural defects in the cell wall resulting from perturbation of pyrimidine biosynthesis allow faster and increased penetration of AmB molecules into the cell membrane. Overall, our work demonstrates that impairment of pyrimidine biosynthesis in C. neoformans could be a potential target for antifungal therapy, either alone or in combination with AmB.
    Keywords: Biology
    E-ISSN: 2379-5042
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  • 8
    Language: English
    In: mBio, 2012, Vol.3(4)
    Description: A critical feature of a potential antimicrobial target is the characteristic of being essential for growth and survival during host infection. For bacteria, genome-wide essentiality screens are usually performed on rich laboratory media. This study addressed whether genes detected in that manner were optimal for the identification of antimicrobial targets since the in vivo milieu is fundamentally different. Mutant derivatives of a clinical isolate of Acinetobacter baumannii were screened for growth on human ascites, an ex vivo medium that reflects the infection environment. A subset of 34 mutants with unique gene disruptions that demonstrated little to no growth on ascites underwent evaluation in a rat subcutaneous abscess model, establishing 18 (53%) of these genes as in vivo essential. The putative gene products all had annotated biological functions, represented unrecognized or underexploited antimicrobial targets, and could be grouped into five functional categories: metabolic, two-component signaling systems, DNA/RNA synthesis and regulation, protein transport, and structural. These A. baumannii in vivo essential genes overlapped poorly with the sets of essential genes from other Gram-negative bacteria catalogued in the Database of Essential Genes (DEG), including those of Acinetobacter baylyi, a closely related species. However, this finding was not due to the absence of orthologs. None of the 18 in vivo essential genes identified in this study, or their putative gene products, were targets of FDA-approved drugs or drugs in the developmental pipeline, indicating that a significant portion of the available target space within pathogenic Gram-negative bacteria is currently neglected. The human pathogen Acinetobacter baumannii is of increasing clinical importance, and a growing proportion of isolates are multiantimicrobial-resistant, pan-antimicrobial-resistant, or extremely resistant strains. This scenario is reflective of the general problem of a critical lack of antimicrobials effective against antimicrobial-resistant Gram-negative bacteria, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter sp., and Escherichia coli. This study identified a set of A. baumannii genes that are essential for growth and survival during infection and demonstrated the importance of using clinically relevant media and in vivo validation while screening for essential genes for the purpose of developing new antimicrobials. Furthermore, it established that if a gene is absent from the Database of Essential Genes, it should not be excluded as a potential antimicrobial target. Lastly, a new set of high-value potential antimicrobial targets for pathogenic Gram-negative bacteria has been identified.
    Keywords: Genes, Bacterial ; Genes, Essential ; Acinetobacter Baumannii -- Genetics ; Ascites -- Microbiology ; Culture Media -- Chemistry
    E-ISSN: 2150-7511
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  • 9
    In: Acta Crystallographica Section F, 01 March 2016, Vol.72(3), pp.179-187
    Description: The enzyme 5‐enolpyruvylshikimate‐3‐phosphate (EPSP) synthase catalyzes the sixth step of the seven‐step shikimate pathway. Chorismate, the product of the pathway, is a precursor for the biosynthesis of aromatic amino acids, siderophores and metabolites such as folate, ubiquinone and vitamin K. The shikimate pathway is present in bacteria, fungi, algae, plants and apicomplexan parasites, but is absent in humans. The EPSP synthase enzyme produces 5‐enolpyruvylshikimate 3‐phosphate and phosphate from phosphoenolpyruvate and shikimate 3‐phosphate a transferase reaction, and is the target of the herbicide glyphosate. The gene encoding EPSP synthase, , has previously been demonstrated to be essential during host infection for the growth and survival of this clinically important drug‐resistant ESKAPE pathogen. Prephenate dehydrogenase is also encoded by the bifunctional gene, but its activity is dependent upon EPSP synthase since it operates downstream of the shikimate pathway. As part of an effort to evaluate new antimicrobial targets, recombinant EPSP (EPSP) synthase, comprising residues Ala301–Gln756 of the gene product, was overexpressed in , purified and crystallized. The crystal structure, determined to 2.37 Å resolution, is described in the context of a potential antimicrobial target and in comparison to EPSP synthases that are resistant or sensitive to the herbicide glyphosate. The crystal structure of 5‐enolpyruvylshikimate‐3‐phosphate (EPSP) synthase, a component of the shikimate pathway, was determined during its evaluation as a target for new antimicrobials effective against multidrug‐resistant, extensively drug‐resistant and pan‐drug‐resistant . This enzyme is essential for the growth and survival of this clinically important pathogen during host infection.
    Keywords: Shikimate Pathway ; Acinetobacter Baumannii ; Essential Genes ; Antibiotic Targets ; Multidrug Resistance ; Epsp Synthase
    ISSN: 2053-230X
    E-ISSN: 2053-230X
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  • 10
    In: Acta Crystallographica Section D, 01 August 2015, Vol.71(8), pp.1736-1744
    Description: is an opportunistic Gram‐negative pathogen that is an important cause of healthcare‐associated infections exhibiting high mortality rates. Clinical isolates of multidrug‐resistant (MDR) and extremely drug‐resistant (XDR) strains are increasingly being observed. Compounding this concern is the dearth of new antibacterial agents in late‐stage development that are effective against MDR and XDR . As part of an effort to address these concerns, two genes ( and ) of the shikimate pathway have previously been determined to be essential for the growth and survival of during host infection ( to be essential ). This study expands upon these results by demonstrating that the gene, encoding shikimate kinase (SK), is also essential in a rat soft‐tissue infection model. The crystal structure of SK in complex with the substrate shikimate and a sulfate ion that mimics the binding interactions expected for the β‐phosphate of ATP was then determined to 1.91 Å resolution and the enzyme kinetics were characterized. The flexible shikimate‐binding domain and LID region are compared with the analogous regions in other SK crystal structures. The impact of structural differences and sequence divergence between SKs from pathogenic bacteria that may influence antibiotic‐development efforts is discussed.
    Keywords: Shikimate Kinase ; Acinetobacter Baumannii ; Essential Gene ; Antibiotic Target ; Multi‐Drug And Extreme Drug Resistance ; Ligand‐Induced Conformational Change ; Enzyme Kinetics
    ISSN: 1399-0047
    ISSN: 09074449
    E-ISSN: 1399-0047
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