Distinctive attributes of β-lactam target proteins in Acinetobacter baumannii relevant to development of new antibiotics

Multi-drug-resistant forms of the Gram-negative pathogen Acinetobacter baumannii are an emerging threat to human health and further complicate the general problem of treating serious bacterial infections. Meeting this challenge requires an improved understanding of the relationships between the structures of major therapeutic targets in this organism and the activity levels exhibited against it by different antibiotics. Here we report the first crystal structures of A. baumannii penicillin-binding proteins (PBPs) covalently inactivated by four β-lactam antibiotics. We also relate the results to kinetic, biophysical, and computational data. The structure of the class A protein PBP1a was solved in apo form and for its covalent conjugates with benzyl penicillin, imipenem, aztreonam, and the siderophore-conjugated monocarbam MC-1. It included a novel domain genetically spliced into a surface loop of the transpeptidase domain that contains three conserved loops. Also reported here is the first high-resolution structure of the A. baumannii class B enzyme PBP3 in apo form. Comparison of this structure with that of MC-1-derivatized PBP3 of Pseudomonas aeruginosa identified differences between these orthologous proteins in A. baumannii and P. aeruginosa. Thermodynamic analyses indicated that desolvation effects in the PBP3 ligand-binding sites contributed significantly to the thermal stability of the enzyme-antibiotic covalent complexes. Across a significant range of values, they correlated well with results from studies of inactivation kinetics and the protein structures. The structural, biophysical, and computational data help rationalize differences in the functional performance of antibiotics against different protein targets and can be used to guide the design of future agents.     

Computational prediction of vibrational spectra of normal and modified DNA nucleobases

Purines, pyrimidines, and the corresponding ribose monophosphates are ubiquitous biomolecules involved in several cellular processes–in DNA and RNA, signaling, and energy transactions. In the new and exciting field of DNA‐inspired nanostructures, they are used as fundamental building blocks. Unique features of the nucleobases are that several tautomeric states are close in energy and the tautomeric equilibria are sensitive to exocyclic substitution and pH. Knowing the exact structure and tautomer(s) at physiological conditions is crucial to understand the substrate specificities and catalytic mechanisms of the many enzymes for which these nucleobases are substrates. Very few spectroscopic methods can distinguish between tautomers and provide solution structures. Vibrational spectroscopy has long been known to be an excellent tool to obtain reliable information on nucleic acids. However, even when good‐quality spectra are available, isotope editing is required to make reliable band assignments and identify structures unequivocally. Density functional theoretical (DFT) methods have become indispensible in assisting the assignment of observed spectra to normal modes, identification of tautomers, and modeling of spectra of isotope‐edited molecules. We review the performance of DFT methods in the prediction of nucleobases and their analogs. We find that even with modest basis sets, trends in vibrational spectra can be predicted adequately and guide assignments to normal modes of the molecule. Shifts in band positions induced upon isotope labeling are reproduced more reliably than the band positions. Scaling considerably improves the agreement between the computed and experimental spectra, but accurate prediction of vibrations of exocyclic groups like CO requires that solvent effects are taken into account. Copyright © 2009 John Wiley & Sons, Ltd.     

Enhanced photodegradation of 2,4-dinitrophenol by n–p type TiO2/BiOI nanocomposite

Photocatalysis has recently been regarded as one of the most viable technologies for water treatment. Scholars all over the world are focusing on nanocomposites for water treatment for efficient and effective sanitization of bodies of water. Because of their high surface area, high chemical reactivity, excellent mechanical strength, low cost, and nanoscale composite materials have enormous potential to purify water in a various way. In this study, n-type TiO₂ was synthesized and tailored to produce a TiO₂/BiOI n–p nanocatalyst for enhanced photodegradation of 2,4-dinitrophenol (2,4-DNP) under UV-A and solar light respectively. Because of the formation of a heterojunction between BiOI and TiO₂, the photocatalytic activity in TiO₂/BiOI absorbs strongly in both the UV and visible regions and it has a lower recombination rate of the e^-/h⁺ pairs. Furthermore, the generation of OH^?, O₂^?– radicals during the oxidation process is attributed to the photodegradation of 2,4-DNP. The results revealed that the TiO₂/BiOI manifest outperformed BiOI and TiO₂ in terms of photocatalytic function. XRD, BET, HR-SEM-EDX with ECM, HR-TEM, FT-IR, PL, and UV-DRS techniques determined the photocatalyst composition. The HR-SEM images clearly showed that the particles are less than 27 ?nm in size. Thus, nanocomposite materials have played an important role in water purification.     

Synthesis of spiropyrazolines

Synthesis of a series of novel 1,3,2′-triphenyl-4-aryl spiropyrazolines [5.4′]-2′-butenolides has been accomplished in good yield by regioselective 1,3-dipolar cycloaddition of diphenylnitrilimine with (E)-3-arylidenebutenolides. X-ray crystal structure analysis of one of the products 4a confirms the structure of the product and the regiochemistry of cycloaddition. © 1998 John Wiley & Sons, Inc. Heteroatom Chem 9:517–522, 1998     

Facile Synthesis and Characterization of Quercetin-Loaded Alginate Nanoparticles for Enhanced In Vitro Anticancer Effect Against Human Leukemic Cancer U937 Cells

Journal of Cluster Science - Nanoparticles synthesized from biopolymers have received attention for their use as biological carriers in the delivery of hydrophobic drugs. Alginate, a marine...     

Highly regio- and stereoselective Michael addition of pseudouridine with propiolates: An efficient method for the synthesis of (E)-pseudouridine-N1-acrylate

The Michael addition of pseudouridine with various propiolates in the presence of DBU as a base and DMF as a solvent is described. It is noteworthy that the reaction is highly regio- and stereoselective and affords (E)-pseudouridine-N1-acrylate in good yields with high purities.     

Inhibition of O-GlcNAcase by a gluco-configured nagstatin and a PUGNAc-imidazole hybrid inhibitor

Synthesis of a PUGNAc-imidazole hybrid and its characterization as an inhibitor of human O-GlcNAcase through enzyme kinetics and X-ray structural analysis.     

Modal interactions and energy transfers in isotropic turbulence as predicted by local energy transfer theory

Energy transfer processes in decaying, three-dimensional, isotropic turbulence are investigated using numerical results from local energy transfer (LET) theory. The study covers a wide range of evolved, microscale Reynolds numbers (5 < R_λ < 250). It is found that the energy transfer is mainly local (between scales of similar size), but there are also some signs of nonlocal transfer at higher Reynolds number. The nature of the underlying triad-wavenumber interactions, on the other hand, seems to depend on both the Reynolds number and the wavenumber range of interest. In the energy containing and dissipation ranges, both local (all three scales of the triad interaction are of comparable size) and nonlocal (one scale is much larger than the remaining two) interactions are important, with the latter becoming more dominant as the Reynolds number increases. But our nonlocal interactions tend to be less severe than those observed by Domaradzki and Rogallo. More significantly, in the inertial range of high Reynolds number flows, the LET theory predicts dominance of local and near-local interactions. While this is contrary to the result from eddy damped quasi-normal Markovian theory that the important triad interactions are mainly nonlocal, it is closer to the Kolmogorov picture of turbulence. Another interesting result is that, despite their inherent differences, the LET theory and the full simulation of Ohkitani and Kida predict inertial-range values for the energy transfer locality function in fairly good agreement, not only with each other, but also with the analytical closure theory result for infinite Reynolds number, stationary turbulence by Kraichnan. The calculated values reveal that the contributions to the net energy transfer are predominantly from near-local interactions (scale ratios ≈ 4), which is indicative of cancellation of large numbers of highly nonlocal interactions.     

Radiation induced preparation of new multifunctional nanobiowebs

New poly(vinylidene fluoride) based multi-functional (electroconductive, bioactive and catalytic) nano-biowebs were prepared through gamma radiation induced formation of silica and gold nanoparticles (Au NPs) within electrospun (poly vinylidene fluoride) nanofiberous membranes. The multifunctional membrane is designated as PVdF@silica/Au ESNFM. The morphology of PVdF@silica/Au ESNFM was examined by field emission scanning electron microscopy. The presence of Au particles was confirmed by energy dispersive x-ray analysis. The crystal structure of Au particles and the formation of silica were confirmed by X-ray diffraction analysis. The multi-functionalities (electroconductive, bioactive and catalytic) of the nano-webs were evaluated by cyclic voltammetry. Cytochrome c was immobilized to generate nano-bioweb (PVdF@silica/Au/cyt c ESNFM), which exhibited electrochemical responses to nitrite ions.