Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria.

Here, we describe the identification of an antibiotic class acting via LpxH, a clinically unexploited target in lipopolysaccharide synthesis. The lipopolysaccharide synthesis pathway is essential in most Gram-negative bacteria and there is no analogous pathway in humans. Based on a series of phenotypic screens, we identified a hit targeting this pathway that had activity on efflux-defective strains of Escherichia coli. We recognized common structural elements between this hit and a previously published inhibitor, also with activity against efflux-deficient bacteria. With the help of X-ray structures, this information was used to design inhibitors with activity on efflux-proficient, wild-type strains. Optimization of properties such as solubility, metabolic stability and serum protein binding resulted in compounds having potent in vivo efficacy against bloodstream infections caused by the critical Gram-negative pathogens E. coli and Klebsiella pneumoniae. Other favorable properties of the series include a lack of pre-existing resistance in clinical isolates, and no loss of activity against strains expressing extended-spectrum-ß-lactamase, metallo-ß-lactamase, or carbapenemase-resistance genes. Further development of this class of antibiotics could make an important contribution to the ongoing struggle against antibiotic resistance.

Gas-Vapor Mixture Temperature in the Near-Surface Layer of a Rapidly-Evaporating Water Droplet.

Mathematical modeling of the heat and mass transfer processes in the evaporating droplet-high-temperature gas medium system is difficult due to the need to describe the dynamics of the formation of the quasi-steady temperature field of evaporating droplets, as well as of a gas-vapor buffer layer around them and in their trace during evaporation in high-temperature gas flows. We used planar laser-induced fluorescence (PLIF) and laser-induced phosphorescence (LIP). The experiments were conducted with water droplets (initial radius 1-2 mm) heated in a hot air flow (temperature 20-500 °C, velocity 0.5-6 m/s). Unsteady temperature fields of water droplets and the gas-vapor mixture around them were recorded. High inhomogeneity of temperature fields under study has been validated. To determine the temperature in the so called dead zones, we solved the problem of heat transfer, in which the temperature in boundary conditions was set on the basis of experimental values.

Conductive Atomic Force Microscopy Study of the Resistive Switching in Yttria-Stabilized Zirconia Films with Au Nanoparticles.

We report on the investigation of the resistive switching (RS) in the ultrathin (≈5 nm in thickness) yttria-stabilized zirconia (YSZ) films with single layers of Au nanoparticles (NPs) by conductive atomic force microscopy (CAFM). Besides the butterfly-type hysteresis loops in the current-voltage (I-V) curves of the contact of the CAFM probe to the investigated film surface corresponding to the bipolar RS, the negative differential resistance (NDR) has been observed in the I-V curves of the AFM probe contact to the YSZ films with Au NPs in the conductive ("ON") state. The NDR has been related to the resonant tunneling of electrons through the size-quantized energy states in the ultrafine (1 to 2 nm in diameter) Au NPs built in the conductive filaments in the YSZ films.

Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors.

A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately leading to compound 13Bh, an extremely potent (K(i)=0.1 nM, EC(50)=4.5 nM) and selective (CC(50) (Huh-7 cells)>50 microM) inhibitor, displaying an excellent PK profile in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration.

The transannular interaction in [2.2]paracyclophane: repulsive or attractive?

The molecular structure and charge density distribution in the crystal of [2.2]paracyclophane derived from the high-resolution single crystal X-ray diffraction data at 100 K is reported together with ab initio calculations of this molecule. Analysis of the atomic, anisotropic displacement parameters in a "rigid-body" model approximation has revealed that the molecule is ordered in the crystal. Topological analysis of the electron density and potential-energy density-distribution functions has demonstrated that there is no "through-space" interaction between the rings in the molecule. The role of the ethylene bridges and distortion of the aromatic desks on the inter-ring interaction are discussed.