Bibliometric analysis of social entrepreneurship in gastronomy tourism

The definition of "entrepreneurship" briefly stands for setting up a new business by taking financial and other risks to gain profits. Phenomenon of "social entrepreneurship" has emerged as a follow up concept of entrepreneurship, as a critical issue in the context of both improvement and wellbeing of societies. Social entrepreneurship focuses on social problems rather than profit maximization and is especially important for gastronomy tourism due to the social local benefits as cultural integration and employment it brings. In order to understand the promising research areas and explore the research gap in the gastronomical social entrepreneurship applications, bibliometric analysis is chosen since studies are limited in the gastronomy tourism as well as social entrepreneurship. The research in subject area consisted on keywords that are used as search items for articles title section to select articles that are more accurate for the aim of the research. The analysis shows that there are 20 articles with the combination of related key word variations. When the methodologies of the related articles is analyzed, it is understood that qualitative research with multiple and comparative case study is chosen for almost all the related articles. The reason might be due to the characteristics of the research topic and novelty, thus, rarity of true to life gastronomical social innovation applications. This study is expected to guide future studies by providing general overview of the studies and the research gap in social entrepreneurship and gastronomy tourism

Combining High-Throughput Synthesis and High-Throughput Protein Crystallography for Accelerated Hit Identification

Protein crystallography (PX) is widely used to drive advanced stages of drug optimization or to discover medicinal chemistry starting points by fragment soaking. However, recent progress in PX could allow for a more integrated role into early drug discovery. Here, we demonstrate for the first time the interplay of high throughput synthesis and high throughput PX. We describe a practical multicomponent reaction approach to acrylamides and ‐esters from diverse building blocks suitable for mmol scale synthesis on 96‐well format and on a high‐throughput nanoscale format in a highly automated fashion. High‐throughput PX of our libraries efficiently yielded potent covalent inhibitors of the main protease of the COVID‐19 causing agent, SARS‐CoV‐2. Our results demonstrate, that the marriage of in situ HT synthesis of (covalent) libraires and HT PX has the potential to accelerate hit finding and to provide meaningful strategies for medicinal chemistry projects

Catch-bond mechanism of the bacterial adhesin FimH

Ligand-receptor interactions that are reinforced by mechanical stress, so-called catch-bonds, play a major role in cell-cell adhesion. They critically contribute to widespread urinary tract infections by pathogenic Escherichia coli strains. These pathogens attach to host epithelia via the adhesin FimH, a two-domain protein at the tip of type I pili recognizing terminal mannoses on epithelial glycoproteins. Here we establish peptide-complemented FimH as a model system for fimbrial FimH function. We reveal a three-state mechanism of FimH catch-bond formation based on crystal structures of all states, kinetic analysis of ligand interaction and molecular dynamics simulations. In the absence of tensile force, the FimH pilin domain allosterically accelerates spontaneous ligand dissociation from the FimH lectin domain by 100,000-fold, resulting in weak affinity. Separation of the FimH domains under stress abolishes allosteric interplay and increases the affinity of the lectin domain. Cell tracking demonstrates that rapid ligand dissociation from FimH supports motility of piliated E. coli on mannosylated surfaces in the absence of shear force

Conformational Switch of the Bacterial Adhesin FimH in the Absence of the Regulatory Domain: Engineering a Minimalistic Allosteric System

For many biological processes such as ligand binding, enzymatic catalysis, or protein folding, allosteric regulation of protein conformation and dynamics is fundamentally important. One example is the bacterial adhesin FimH, where the C-terminal pilin domain exerts negative allosteric control over binding of the N-terminal lectin domain to mannosylated ligands on host cells. When the lectin and pilin domains are separated under shear stress, the FimH-ligand interaction switches in a so-called catch-bond mechanism from low to high affinity state. So far, it has been assumed that the pilin domain is essential for the allosteric propagation within the lectin domain that would otherwise be conformationally rigid. To test this hypothesis, we generated mutants of the isolated FimH lectin domain and characterized their thermodynamic, kinetic, and structural properties using ITC, SPR, NMR and X-ray techniques. Intriguingly, some of the mutants mimicked the conformational and kinetic behaviors of the full-length protein and, even in absence of the pilin domain, conducted the crosstalk between allosteric sites and the mannoside binding pocket. Thus, these mutants represent a minimalistic allosteric system of FimH, useful for further mechanistic studies and antagonist design

FimH antagonists - solubility vs. permeability

Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) are among the most prevalent infections worldwide. Since frequent antibiotic treatment favors the emergence of antibiotic resistance, efficient non-antibiotic strategies are urgently needed. The first step of the pathogenesis of UTI is the bacterial adherence to urothelial host cells, a process mediated by the mannose-binding adhesin FimH located at the tip of bacterial pili. In a preliminary study, biphenyl α-d-mannopyranosides with an electron-withdrawing carboxylate on the aglycone were identified as potent FimH antagonists. Although passive permeability could be established by masking the carboxylate as an ester, insufficient solubility and fast hydrolysis did not allow to maintain the therapeutic concentration in the bladder for the requested period of time. By modifying the substitution pattern, molecular planarity and symmetry of the biphenyl aglycone could be disrupted leading to improved solubility. In addition, when heteroatoms were introduced to the aglycone, antagonists with further improved solubility, metabolic stability as well as passive permeability were obtained. The best representative, the pyrrolylphenyl mannoside 42f exhibited therapeutic urine concentration for up to 6 h and is therefore a promising oral candidate for UTI prevention and/or treatment

Urinary Tract Infection: Which Conformation of the Bacterial Lectin FimH Is Therapeutically Relevant?

Frequent antibiotic treatment of urinary tract infections has resulted in the emergence of antimicrobial resistance, necessitating alternative treatment options. One such approach centers around FimH antagonists that block the bacterial adhesin FimH, which would otherwise mediate binding of uropathogenic Escherichia coli to the host urothelium to trigger the infection. Although the FimH lectin can adopt three distinct conformations, the evaluation of FimH antagonists has mainly been performed with a truncated construct of FimH locked in one particular conformation. For a successful therapeutic application, however, FimH antagonists should be efficacious against all physiologically relevant conformations. Therefore, FimH constructs with the capacity to adopt various conformations were applied. By examining the binding properties of a series of FimH antagonists in terms of binding affinity and thermodynamics, we demonstrate that depending on the FimH construct, affinities may be overestimated by a constant factor of 2 orders of magnitude. In addition, we report several antagonists with excellent affinities for all FimH conformations