26 research outputs found
Design, synthesis, crystal structures and antimicrobial activity of sulfonamide boronic acids as beta-lactamase inhibitors
No full textβ-Lactamase-mediated resistance to β-lactam antibiotics threatens our antibiotic armamentarium. We investigated a new series of sulfonamide boronic acids against AmpC, a class C beta-lactamase that confers extended spectrum resistance to beta-lactams worldwide. Previously, we had explored transition-state analog carboxamide boronic acids and another, unrelated series of non-covalent inhibitors bearing sulfonamide side chains. Merging these two series resulted in boronic acids that differed in the replacement of the canonical carboxamide, which was inserted to mimic the amide in C6/C7 of peniccilins and cephalosporins, with a sulfonamide. Surprisingly, these sulfonamides had a highly distinct SAR from the carboxamides, with Ki values 23 times better for small analogs and Ki values 10 to 20 times worse than the carboxamide congener for larger molecules. X-ray crystal structures of three of the new sulfonamides explain this dramatically changed SAR. The most potent of these beta-lactamase inhibitors were tested in cell culture and showed good ability to reverse beta-lactamase mediated resistance to third generation cephalosporins
The Challenges to Improving Public Services and Judicial Operations: A unique balance between pursuing justice and public service in Indonesia
No full textThis chapter explores judicial perspectives on sentencing minor drug offenders in Indonesia. As a basis for the framework for this study, a concept of Goffman on dramaturgy was used to explain the dramaturgical competence of the panel judges in their attempts to show accountability to their audiences (i.e., the sphere of politics, the public, and religion). Conceptualisation of this study stems from this author former self-identity as a judge but also from the author biography since the author more familiar with the practical pressure and challenges of lower court judges. This chapter contributes to knowledge by considering that the judicial awareness of the issues surrounding justice and public acceptance led to the situation where they were attempting to present a unique balance between pursuing justice and public service
Examining the Feasibility of Using Free Energy Perturbation (FEP+) in Predicting Protein Stability
No full textComprehensive mechanistic analysis of hits from high-throughput and docking screens against β-lactamase
No full textHigh-throughput screening (HTS) is widely used in drug discovery. Especially for screens of unbiased libraries, false positives can dominate “hit lists”; their origins are much debated. Here we determine the mechanism of every active hit from a screen of 70,563 unbiased molecules against β-lactamase using quantitative HTS (qHTS). Of the 1274 initial inhibitors, 95% were detergent-sensitive and were classified as aggregators. Among the 70 remaining were 25 potent, covalent-acting β-lactams. Mass spectra, counter-screens, and crystallography identified 12 as promiscuous covalent inhibitors. The remaining 33 were either aggregators or irreproducible. No specific reversible inhibitors were found. We turned to molecular docking to prioritize molecules from the same library for testing at higher concentrations. Of 16 tested, 2 were modest inhibitors. Subsequent X-ray structures corresponded to the docking prediction. Analog synthesis improved affinity to 8 μM. These results suggest that it may be the physical behavior of organic molecules, not their reactivity, that accounts for most screening artifacts. Structure-based methods may prioritize weak-but-novel chemotypes in unbiased library screens
Sick building symptoms among hospital workers associated with indoor air quality and personal factors
No full textThis study assesses the interior air quality and infective factors in a hospital in Turkey to provide data about air quality to protect hospital workers. This study measured indoor air quality in eight different locations in a hospital, including particulate matter (PM2.5 and PM1), carbon dioxide, carbon monoxide, temperature, humidity and microbiological matter. The highest PM2.5 and PM1 concentrations were in emergency service, and the highest CO2 was measured in the paediatric clinic. The poor interior air quality results are the most important cross-sectional data. For all participants, the prevalence of eye, upper respiratory tract, lower respiratory tract, skin and non-specific sick building syndrome symptoms were 23.0%, 40.7%, 22.5%, 36.3% and 63.7%, respectively. When sick building syndrome symptoms and environmental factors were investigated, skin symptoms increased 1.82 times in areas with stagnant air flow (p = 0.046; OR = 1.823; 95% CI: 1.010–3.290). Non-specific symptoms increased 2.17 times in locations with dry indoor air (p = 0.039; OR = 2.176; 95% CI: 1.041–4.549). Hospital workers are exposed to conditions that may increase the risk of a variety of sick building syndrome symptoms. Although the air quality measurements were not above the recommended limits in the hospital, long-term exposures should be considered for those experiencing sick building syndrome-related symptoms. © The Author(s) 2019
<i>O</i>-Aryloxycarbonyl Hydroxamates: New β-Lactamase Inhibitors That Cross-Link the Active Site
No full textO-Aryloxycarbonyl hydroxamates represent a new class of β-lactamase inhibitors. N-Benzyloxycarbonyl-O-(phenoxycarbonyl) hydroxylamine, for example, inactivates the class C Enterobacter cloacae P99 β-lactamase with a rate constant of 6.1 × 103 s-1 M-1; approximately two turnover events accompany the inhibition. N-Benzyloxycarbonyl-O-[(3-carboxyphenoxy)carbonyl] hydroxylamine is comparably effective. These compounds also inactivate the class A TEM β-lactamase. A crystal structure of the inactivated AmpC enzyme, another class C β-lactamase, reveals that the active site has become cross-linked by a carbamate bridge spanning Ser64, the active site nucleophile, and Lys315, a conserved active site residue
Novel inhibitors of an emerging target in Mycobacterium tuberculosis; substituted thiazolidinones as inhibitors of dTDP-rhamnose synthesis
No full textThe emergence of multi-drug resistant tuberculosis, coupled with the increasing overlap of the AIDS and tuberculosis pandemics has brought tuberculosis to the forefront as a major worldwide health concern. In an attempt to find new inhibitors of the enzymes in the essential rhamnose biosynthetic pathway, a virtual library of 2,3,5 trisubstituted-4-thiazolidinones was created. These compounds were then docked into the active site cavity of 6'hydroxyl; dTDP-6-deoxy-D-xylo-4-hexulose 3,5-epimerase (RmlC) from Mycobacterium tuberculosis. The resulting docked conformations were consensus scored and the top 5% were slated for synthesis. Thus far, 94 compounds have been successfully synthesized and initially tested. Of those, 30 (32%) have > or =50% inhibitory activity (at 20 microM) in the coupled rhamnose synthetic assay with seven of the 30 also having modest activity against whole-cell M. tuberculosis
