1,721,235 research outputs found
3-Aminophenylboronic acid derivative inhibitors of beta-lactamases, their preparation, and their therapeutic use.
No full textThe invention provides novel non-/9-lactam inhibitors of ^-lactamases. In particular, the invention provides such inhibitors which are boronic acids of formula (I) which is set forth in the specification. These compounds may be used with /Mactam antibiotics to treat /J-lactam-antibiotic-resistant bacterial infections. Finally, the invention provides a pharmaceutical composition comprising these compounds
Sulfonamido-substituted boronic acids as β-lactamase inhibitors for treatment of antibiotic-resistant bacterial infections
No full textDisclosed herein inter alia are Boron containing compounds and methods for treating infections related to antibiotic resistant microorganisms
Crystallographic studies of novel inhibitors of [beta]-lactamases
No full textBacterial expression of -lactamases is the most widespread resistance mechanism to -lactam antibiotics. There is a pressing need for novel, non- -lactam inhibitors of these enzymes [1]. Our efforts to overcome bacterial resistance mechanisms have been directed towards novel, non -lactam inhibitors of AmpC -lactamase, a class C enzyme responsible of resistance to antibiotics treatment in gram- negative bacteria.
Through a structure-based approach, we discover novel inhibitors for this enzyme, with covalent mechanism of action such as boronic acid derivatives and with no-covalent, competitive mechanism of action, such as thiophene-2-carboxylic acid derivative [2].
In one case we were able to extend the inhibitory activity towards class A -lactamases, obtaining a broad spectrum, highly potent inhibitor.
Some inhibitors were active in cell culture, reversing resistance to the third generation cephalosporin ceftazidime in bacterial pathogens expressing AmpC and did not up-regulate -lactamase expression in cell culture.
The structure-based design, synthesis, biological evaluation and the crystallographic studies of such novel inhibitors will be described.
[1] Cosgrove S., Carmeli Y., Clin. Infect. Dis., 2003, 36, 1433-1437. [2] Tondi D., Morandi F., Bonnet R., Costi M. P., Shoichet B. K., J. Am. Chem. Soc., 2005, 127(13), 4632-4639.
Keywords: enzyme inhibition, drug resistance, X-ray complexe
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Variations on the Author
Get PDF“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
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe 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
Targeting Class A and C Serine β-Lactamases with a Broad-Spectrum Boronic Acid Derivative
Get PDFProduction of β-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight β-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serine-based BLs. Starting from benzo(b)thiophene-2-boronic acid (BZBTH2B), a nanomolar non-β-lactam inhibitor of AmpC that can potentiate the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria, we designed a novel broad-spectrum nanomolar inhibitor of class A and C BLs. Structure-based drug design (SBDD), synthesis, enzymology data, and X-ray crystallography results are discussed. We clarified the inhibitor binding geometry responsible for broad-spectrum activity vs serine-active BLs using double mutant thermodynamic cycle studies
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Pharmacological organization of proteins: Towards an understanding of biological symbolism and protein relationships from the perspective of ligands
Get PDFRelating proteins based on the similarity of the ligands that bind to and modulate through them is a field that has its basis in classical pharmacology when ligands were tested for phenotypic effects on whole tissues, organs or organisms. We take a ligand-focused view of biology to build protein-protein relationships by describing proteins not by their sequence, structure or function, but by their ligand sets. A systematic approach to relate proteins together both within a family and between families are described. The engine we use to drive a pharmacological organization of proteins is the Similarity Ensemble Approach (SEA) using ligands from ChEMBL to create sets for each protein target as input. We use the output from SEA as a similarity metric to relate proteins pharmacologically. Family A G protein-coupled receptors (GPCRs) was a family of proteins we first aimed to reorganize pharmacologically. Compared to a sequence based organization of GPCRs, the ligand based organization had a much different arborization of its dendrogram with some GPCRs moving away from their "commonly" related GPCRs while some "distantly" related GPCRs were brought together because they shared common ligands. The pharmacological organization led us to predict for testing GPCRs that were similar based on pharmacology but different from a sequence view. We confirmed three new pairs of GPCRs that were now linked by a new, shared ligand where they previously had no known shared ligands. Moving beyond GPCRs, we sought a deeper biological relationship between proteins and protein families we related pharmacologically by finding new protein links that not only could potentially share a ligand, based on our predictions, but also shared a phenotype, function, or are implicated in similar diseases. The proteins we related in this manner were also not from the same sequence or structural family but different from classical bioinformatics metrics. The assertion is that because there is a limited number of endogenous signaling molecules, their evolution is almost frozen and therefore, cells and their proteins must evolve and adapt around signaling molecules on top of functioning through them. Relating proteins pharmacologically and phenotypically is explored
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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