New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria

BACKGROUND: Penicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs beta-lactams inhibit transpeptidase activity of PBPs by forming a covalent penicilloyl-enzyme complex that blocks the normal transpeptidation reaction; this finally results in bacterial death. In some resistant bacteria the resistance is acquired by active-site distortion of PBPs, which lowers their acylation efficiency for beta-lactams. To address this problem we focused our attention to discovery of novel noncovalent inhibitors of PBPs. METHODOLOGY/PRINCIPAL FINDINGS: Our in-house bank of compounds was screened for inhibition of three PBPs from resistant bacteria: PBP2a from Methicillin-resistant Staphylococcus aureus (MRSA), PBP2x from Streptococcus pneumoniae strain 5204, and PBP5fm from Enterococcus faecium strain D63r. Initial hit inhibitor obtained by screening was then used as a starting point for computational similarity searching for structurally related compounds and several new noncovalent inhibitors were discovered. Two compounds had promising inhibitory activities of both PBP2a and PBP2x 5204, and good in-vitro antibacterial activities against a panel of Gram-positive bacterial strains. CONCLUSIONS: We found new noncovalent inhibitors of PBPs which represent important starting points for development of more potent inhibitors of PBPs that can target penicillin-resistant bacteria.Eur-Intafa

Crystalline Ultrasmooth Self-Assembled Monolayers of Alkylsilanes for Organic Field-Effect Transistors

Crystalline self-assembled monolayers (SAMs) of organosilane compounds such as octadecyltrimethoxysilane (OTMS) and octadecyltrichlorosilane (OTCS) were deposited by a simple, spin-casting technique onto Si/SiO2 substrates. Fabrication of the OTMS SAMs and characterization using ellipsometry, contact angle, atomic force microscopy (AFM), grazing angle attenuated total reflectance Fourier transform infrared (GATR-FTIR) spectroscopy and grazing incidence X-ray diffraction (GIXD) are described. The characterization confirms that these monolayers exhibit a well-packed crystalline phase and a remarkably high degree of smoothness. Semiconductors deposited by vapor deposition onto the crystalline OTS SAM grow in a favorable two-dimensional layered growth manner which is generally preferred morphologically for high charge carrier transport. On the OTMS SAM treated dielectric, pentacene OFETs showed hole mobilities as high as 3.0 cm(2/)V.s, while electron mobilities as high as 5.3 cm(2/)V.s were demonstrated for C-60.X11370344sciescopu

Interplay between Energetic and Kinetic Factors on the Ambient Stability of n-Channel Organic Transistors Based on Perylene Diimide Derivatives

The effects of the interplay between energetic and kinetic factors on the air stability of n-channel organic thin-film transistors (OTFTs) were studied using two perylene diimide (PDI) compounds with distinctly different lowest unoccupied molecular orbital (LUMO) levels. On the basis of the empirical energy level windows, one compound (N,N'-bis(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-3,4:9,10-tetracarboxylic acid diimide (PDI-F): -3.84 eV) is at the onset region for air stability, whereas the other (N,N'-bis(cyclohexyl)-1,7-dicyano-perylene-3,4:9,10-tetracarboxylic acid diimide (PDI-CN2): -4.33 eV) is in the air-stable region. Charge-transport behaviors under an inert atmosphere and in air were investigated as a function of active layer thickness. Charge transport in air was greatly affected by the active layer thickness for both compounds, an effect that has been overlooked so far. The ambient stability of the air-unstable PDI-F TFTs increased significantly for thicknesses over similar to 10 monolayers (ML). Surprisingly, the previously considered "air-stable" PDI-CN2 TFTs were not stable in air if the active layer thickness was less than similar to 4 ML. The molecular packing and orientation of the PDI thin Films were investigated using grazing incidence X-ray diffraction (GIXD) and near-edge X-ray absorption fine structure (NEXAFS). We found that the minimum thickness required for air stability is closely related to the LUMO level, film morphology, and film growth mode.X116255sciescopu

The Role of OTS Density on Pentacene and C-60 Nucleation, Thin Film Growth, and Transistor Performance

In organic thin film transistors (OTFTs), charge transport occurs in the first few monolayers of the semiconductor near the semiconductor/dielectric interface. Previous work has investigated the roles of dielectric surface energy, roughness, and chemical functionality on performance. However, large discrepancies in performance, even with apparently identical surface treatments, indicate that additional surface parameters must be identified and controlled in order to optimize OTETs. Here, a crystalline, dense octadecylsilane (OTS) surface modification layer is found that promotes two-dimensional semiconductor growth. Higher mobility is consistently achieved for films deposited on crystalline OTS compared to on disordered OTS, with mobilities as high as 5.3 and 2.3 cm(2)V(-1) s(-1) for C-60 and pentacene, respectively. This is a significant step toward morphological control of organic semiconductors which is directly linked to their thin film carrier transport.X11170174sciescopu

Quality circles and human rights: tackling the universalism and cultural relativism divide

The implementation of international human rights law has traditionally been undermined by the dichotomy between universalism and cultural relativism. Some groups regard human rights as more reflective of other culture’s and are unwilling to subscribe to them. One response to this is to enable groups to take co-ownership of human rights. Quality Circles based on institutions and technology, and the collaboration they encourage, provide one such means for doing so. What is required is for states to facilitate rather than undermine and censor these processes. Human Rights Quality Circles at different levels represent one way in which the cultural relativism and universalism division can be addressed, particularly in an ever-globalising world