Non-bisphosphonate inhibitors of isoprenoid biosynthesis identified via computer-aided drug design.

The relaxed complex scheme, a virtual-screening methodology that accounts for protein receptor flexibility, was used to identify a low-micromolar, non-bisphosphonate inhibitor of farnesyl diphosphate synthase. Serendipitously, we also found that several predicted farnesyl diphosphate synthase inhibitors were low-micromolar inhibitors of undecaprenyl diphosphate synthase. These results are of interest because farnesyl diphosphate synthase inhibitors are being pursued as both anti-infective and anticancer agents, and undecaprenyl diphosphate synthase inhibitors are antibacterial drug leads

Immuno-antibiotics: Targeting microbial metabolic pathways sensed by unconventional T cells

Human Vγ9/Vδ2 T cells, mucosal-associated invariant T (MAIT) cells and other unconventional T cells are specialised in detecting microbial metabolic pathway intermediates that are absent in humans. The recognition by such semi-invariant innate-like T cells of compounds like (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), the penultimate metabolite in the MEP isoprenoid biosynthesis pathway, and intermediates of the riboflavin biosynthesis pathway and their metabolites allows the immune system to rapidly sense pathogen-associated molecular patterns that are shared by a wide range of micro-organisms. Given the essential nature of these metabolic pathways for microbial viability, they have emerged as promising targets for the development of novel antibiotics. Here, we review recent findings that link enzymatic inhibition of microbial metabolism with alterations in the levels of unconventional T cell ligands produced by treated micro-organisms that have given rise to the concept of ‘immuno-antibiotics’: combining direct antimicrobial activity with an immunotherapeutic effect via modulation of unconventional T cell responses

Iron Porphyrin Carbenes As Catalytic Intermediates: Structures, Mössbauer and NMR Spectroscopic Properties, and Bonding

Iron porphyrin carbenes (IPCs) are thought to be intermediates involved in the metabolism of various xenobiotics by cytochrome P450, as well as in chemical reactions catalyzed by metalloporphyrins and engineered P450s. While early work proposed IPCs to contain FeII, more recent work invokes a double-bond description of the iron–carbon bond, similar to that found in FeIV porphyrin oxenes. Reported herein is the first quantum chemical investigation of IPC Mössbauer and NMR spectroscopic properties, as well as their electronic structures, together with comparisons to ferrous heme proteins and an FeIV oxene model. The results provide the first accurate predictions of the experimental spectroscopic observables as well as the first theoretical explanation of their electrophilic nature, as deduced from experiment. The preferred resonance structure is FeII←{:C(X)Y}0 and not FeIV{C(X)Y}2−, a result that will facilitate research on IPC reactivities in various chemical and biochemical systems

Oxygen-17 Cross-Polarization NMR Spectroscopy of Inorganic Solids*

We have obtained I70 nuclear magnetic resonance spectra of a variety of '70-labeled solids (Mg(OH)z, Ca(OH)*, boehmite (AlO(C talc (Mg3Si.,0,,(OH)2), (C6H,),SiOH, and amorphous Si02) using high-field static and "magioangle" sample spinning techniques, together with 'H cross polarization and dipolar decoupling. Our results show that large cross-polarization enhancements can be obtained and that reliable second-order quatipolar powder lineshapes can be observed under cross-polarization conditions. We have also investigated the dynamics of cross polarization for several samples, including measurements of cross-relaxation rates and 'H and I70 rotating-frame spin-lattice relaxation times. We show that rapid I70 rotating-frame spin-lattice relaxation reduces the cross-polarization enhancement in some cases and that differences in cross-relaxation rates can be used to "edit" spectra by selectively enhancing protonated oxygen resonances (in general, hydroxide versus oxide ions, in inorganic solids). When applied to high surface area metal oxides such as amorphous silica, this selectivity enables the observation of resonances from surface hydroxyl groups that are difficult to detect by conventional "0 NMR. Overall, the crosspolarization approach appears to have considerable utility for aiding in the interpretation of "0 NMR spectra of complex inorganic solids. 0 1988 Academic PBS, Inc

Coverage dependence of co surface diffusion on pt nanoparticles: An ec-nmr study

We have studied the effects of CO surface coverage on the diffusion rates of CO adsorbed on commercial Pt-black in sulfuric acid media by using 13 C electrochemical nuclear magnetic resonance (EC-NMR) spectroscopy in the temperature range 253-293 K. The temperature range chosen for these measurements was such that the electrolyte is in a liquid-like and liquid environment. For CO coverage between θ ) 1.0 and 0.36, the CO diffusion coefficients (D CO ) follow a typical Arrhenius behavior and both the activation energies (E d ) as well as the pre-exponential factors (D CO 0 ) show CO coverage dependence. For partially CO covered samples, E d decreases linearly with increasing CO coverage, indicating that the repulsive CO-CO interactions exert a stronger influence on the coverage dependence of the activation energy than does the nature of the CO adlayer structure. On the other hand, D CO 0 shows an exponential decrease with increasing CO coverage, consistent with the free site hopping model [Gomer, R. Rep. Prog. Phys. 1990, 53, 917] as the major mechanism for surface diffusion of CO at partial coverages, unlike the situation found with a fully CO covered surface [Kobayashi et al., J. Am. Chem. Soc., 2005, 127, 14164]. Overall, these results are of interest since they improve our understanding of the surface dynamics of molecules at electrochemical interfaces, and may help facilitate better control of fuel cell reactions in which the presence of surface CO plays a crucial role in controlling electrocatalytic reaction rates