1,721,046 research outputs found
Ten Years with New Delhi Metallo-β-lactamase-1 (NDM-1): From Structural Insights to Inhibitor Design
No full textThe worldwide emergence of New Delhi metallo-β-lactamase-1 (NDM-1) as a carbapenemase able to hydrolyze nearly all available β-lactam antibiotics has characterized the past decade, endangering efficacious antibacterial treatments. No inhibitors for NDM-1 are available in therapy, nor are promising compounds in the pipeline for future NDM-1 inhibitors. We report the studies dedicated to the design and development of effective NDM-1 inhibitors. The discussion for each agent moves from the employed design strategy to the ability of the identified inhibitor to synergize β-lactam antibiotics. A structural analysis of NDM-1 mechanism of action based on selected X-ray complexes is also reported: the intrinsic flexibility of the binding site and the comparison between penicillin/cephalosporin and carbapenem mechanisms of hydrolysis are evaluated. Despite the valuable progress in terms of structural and mechanistic information, the design of a potent NDM-1 inhibitor to be introduced in therapy remains challenging. Certainly, only the deep knowledge of NDM-1 architecture and of the variable mechanism of action that NDM-1 employs against different classes of substrates could orient a successful drug discovery campaign
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Defeat Staphylococcus aureus by targeting iron acquisition systems
No full textBackground and Aims
To tackle antibiotic resistance and the appearance of multidrug-resistant (MDR) Staphylococcus aureus strains, one interesting approach is interfering with iron uptake and metabolism as possible drug targets. To overcome the host iron withholding defenses and establish an infection, S. aureus secretes two siderophores, namely Staphyloferrin A (SA) and Staphyloferrin B (SB), with the latter being produced only by the most invasive, coagulase-positive strains.
The aim of this study was to investigate siderophore-mediated iron uptake in S. aureus, to validate the selection of specific molecules able to block this mechanism.
Methods
We have determined the best growth conditions to investigate the effect of iron starvation in S. aureus, represented by the Chelex®-treated chemically-defined Tris Minimal Succinate (cTMS) medium, in which high levels of siderophore were produced by S. aureus, thus confirming that iron is perceived as a limiting nutrient in cTMS.
Results
Siderophore-defective strains, namely ΔsbnA, ΔsfaD and ΔsbnAΔsfaD deletion mutants, unable to produce SB, SA or both, respectively, were successfully generated, and their contribution to S. aureus growth was investigated. Both SA and SB were necessary to support Sa growth under iron-deprived conditions. Interestingly ΔsbnAΔsfaD was unable to grow in synthetic media mimicking biological fluids (i.e., human serum). Within the ERASE project (PRIN2020AE3LTA), the SbnA enzyme, involved in SB biosynthesis, was characterized in vitro and specific inhibitors were identified.
Conclusions
These inhibitors were found to affect siderophore production in S. aureus, paving the way for the discovery of effective molecules able to interfere with iron acquisition, that might find application as innovative antimicrobials
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Investigating the energetic principles that govern the amino acid-nucleotide base recognition process in protein-DNA complexes
No full textAppropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
A non Newtonian empirical approach for the evaluation of protein-DNA binding free energy and molecular recognition
No full textChemogenomics of pyridoxal 5'-phosphate dependent enzymes.
No full textPyridoxal 5′-phosphate (PLP) dependent enzymes comprise a large family that plays key roles in amino acid metabolism and are acquiring an increasing interest as drug targets. For the identification of compounds inhibiting PLP-dependent enzymes, a chemogenomics-based approach has been adopted in this work. Chemogenomics exploits the information coded in sequences and three-dimensional structures to define pharmacophore models. The analysis was carried out on a dataset of 65 high-resolution PLP-dependent enzyme structures, including representative members of four-fold types. Evolutionarily conserved residues relevant to coenzyme or substrate binding were identified on the basis of sequence-structure comparisons. A dataset was obtained containing the information on conserved residues at substrate and coenzyme binding site for each representative PLP-dependent enzyme. By linking coenzyme and substrate pharmacophores, bifunctional pharmacophores were generated that will constitute the basis for future development of small inhibitors targeting specific PLP-dependent enzymes.
Read More: http://informahealthcare.com/doi/abs/10.3109/14756366.2011.64330
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