Antifungal properties and target evaluation of three putative bacterial histidine kinase inhibitors.
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Histidine protein kinases have been explored as potential antibacterial drug targets. The recent identification of two-component histidine kinases in fungi has led us to investigate the antifungal properties of three bacterial histidine kinase inhibitors (RWJ-49815, RWJ-49968, and RWJ-61907). All three compounds were found to inhibit growth of the Saccharomyces cerevisiae and Candida albicans strains, with MICs ranging from 1 to 20 microg/ml. However, deletion of SLN1, the only histidine kinase in S. cerevisiae, did not alter drug efficacy. In vitro kinase assays were performed by using the Sln1 histidine kinase purified from bacteria as a fusion protein to glutathione S-transferase. RWJ-49815 and RWJ-49968 inhibited kinase a 50% inhibitory concentration of 10 microM, whereas RWJ-61907 failed to inhibit at concentrations up to 100 microM. Based on these results, we conclude that these compounds have antifungal properties; however, their mode of action appears to be independent of histidine kinase inhibition. (+info)
Enhanced uptake of [11C]TPMP in canine brain tumor: a PET study.
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In vitro studies have demonstrated the membrane potential-dependent enhanced uptake of phosphonium salts, including [3H]triphenylmethylphosphonium (TPMP), into mitochondria of carcinoma and glioma-derived tumor cells, suggesting the potential use of phosphonium salts as tracers for tumor imaging. This study characterizes the in vivo uptake of [11C]TPMP in canine brain glioma using PET. METHODS: Dynamic paired PET studies of [11C]TPMP followed by [68Ga]ethylenediaminetetraacetic acid (EDTA) were performed 4 d before and 9 d after tumor cell inoculation. Graphical analysis was used to evaluate [11C]TPMP retention in tumor tissue. Distribution of tracer uptake was compared with tumor histological sections. RESULTS: [11C]TPMP exhibited enhanced uptake and prolonged retention in tumor cells. Patlak plot was linear over the 20- to 95-min postinjection period (r = 0.97 +/- 0.1). [68Ga]EDTA exhibited a gradual washout from the tumor tissue. The tumor-to-normal brain uptake ratio at 55 to 95 min postinjection was 47.5 for [11C]TPMP and 8.1 for [68Ga]EDTA. Qualitative comparison with histological sections indicated that [11C]TPMP enhanced uptake was restricted to the tumor area. CONCLUSION: The enhanced uptake and prolonged retention in tumor suggest [11C]TPMP as a promising means for imaging of gliomas in dogs. The need for studies in humans is indicated. (+info)
Trityl mass-tags for encoding in combinatorial oligonucleotide synthesis.
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Combinatorial libraries of oligonucleotides on beads were synthesised by a split-and-mix strategy using 5'-DMTr- or 5'-Fmoc- nucleoside phosphoramidites. Trityl moieties with different masses were used to encode for the bases coupled at each step in the synthesis of oligonucleotides selected by hybridisation from the libraries. Tags orthogonal to the nucleotides added were produced by coupling amines of different MW to an activated carboxyl group(s) on the trityl moiety. Tags can be released from the support by laser irradiation and measured directly by TOF without matrix. Alternatively, they may be released by an acidic treatment and then analysed by (MA)LDI-TOF. (+info)
A large-scale snail control trial with trifenmorph in the Gezira irrigation scheme, Sudan.
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A large-scale field trial was carried out during December 1973 to assess the effect of trifenmorph on Bulinus truncatus and Biomphalaria pfeifferi in 379 000 feddans ( approximately 159 000 ha) of the Gezira irrigation system in the Sudan. The commercial formulation used (Frescon) is an emulsifiable concentrate containing 16.5% trifenmorph. Five dispensers were used to add the commercial product to the water continuously for 7.5 days; 18 121 litres were used to treat 28.4 million m(3) of water. In addition, each minor canal was hand-sprayed from the tail to 300 m upstream of the last open field outlet pipe; 360 litres of the commercial formulation were used for this operation.A minimum concentration of 0.035 mg trifenmorph per litre of water was produced at the head of each minor canal. The use of caged snails showed that a concentration as low as 0.015 mg/litre was sufficient to produce 100% mortality in B. truncatus in 7.5 days; this is equivalent to a concentration x time product of 0.12 mg/litre days. (+info)
Factors that determine the plasma-membrane potential in bloodstream forms of Trypanosoma brucei.
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The plasma-membrane potential (Delta(psi)p) in bloodstream forms of Trypanosoma brucei was studied using several different radiolabelled probes: 86Rb+ and [14C]SCN- were used to report Delta(psi)p directly because they distribute in easily measured quantities across the plasma membrane only, and [3H]methyltriphenylphosphonium (MePh3P+) was used to report Delta(psi)p only when Delta(psi)m had been abolished with FCCP because it reports the algebraic sum of the two potentials when used alone. The unperturbed Delta(psi)p had a value of -82 mV and was found to be essentially identical with, and determined almost completely by, the potassium diffusion potential, as evidenced by: (a) the lack of effect of valinomycin on the value obtained under appropriate conditions when any of these probes were used; (b) the close agreement of this measured value with that predicted from the measured distribution of K+ across the plasma membrane (-76 mV); (c) the large effect of changes in the extracellular K+ concentration by substitution with Na+ on Delta(psi)p together with the complete lack of effect of substitution of extracellular Na+ by the choline cation or substitution of extracellular Cl- by the gluconate anion on Delta(psi)p. The contribution to Delta(psi)p by electrogenic pumping of Na+/K+-ATPase was found to be small (of the order of 6 mV). H+ was not found to be pumped across the plasma membrane or to contribute to Delta(psi)p. (+info)
Occurrence of Tris(4-chlorophenyl)methane, tris(4-chlorophenyl)methanol, and some other persistent organochlorines in Japanese human adipose tissue.
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Tris(4-chlorophenyl)methane (TCPMe) and tris(4-chlorophenyl)methanol (TCPMOH) are among the most recently identified environmental contaminants. Despite their widespread contamination in the marine environment, human exposure to these compounds remains relatively unknown. We determined the concentrations of TCPMe, TCPMOH, and other persistent organochlorines such as polychlorinated biphenyls (PCBs), DDT and its metabolites, hexachlorocyclohexane isomers, hexachlorobenzene, and chlordane compounds (CHLs) in human adipose tissue from Japan. TCPMe and TCPMOH were detected in all of the adipose samples analyzed; the concentrations ranged from 2.5-21 and 1.1-18 ng/g lipid weight, respectively. Concentrations of TCPMe and TCPMOH in humans were less than those reported in marine mammals, suggesting the possibility of metabolism and elimination of these compounds by humans. Significant correlation between TCPMe and TCPMOH with concentrations of DDT and its metabolites in human adipose tissues suggested that exposure to DDT is the source of TCPMe and TCPMOH in humans. The age- and sex-dependent accumulation of TCPMe and TCPMOH as well as other organochlorines was less pronounced. Results for other organochlorines indicated that recent contamination status of PCBs in human samples from Japan was higher than that in developing countries, whereas DDT contamination is lower. Greater concentrations of CHLs in human adipose tissue from Japan than in those from other countries suggest that continuous monitoring of CHLs in humans in Japan is necessary. To our knowledge, this is the first study on the accumulation of TCPMe and TCPMOH in human adipose tissue. (+info)
The mechanism of action of inhibitors of bacterial two-component signal transduction systems.
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Two-component signal transduction systems allow bacteria to sense and respond rapidly to changes in their environment leading to specific gene activation or repression. These two-component systems are integral in the ability of pathogenic bacteria to mount and establish a successful infection within the host and, consequently, have been recognized as targets for new anti-microbial agents. In this paper, we define the site and mechanism of action of several previously identified inhibitors of bacterial two-component systems. We show that the most potent inhibitors target the carboxyl-terminal catalytic domain of the sensor kinase and exert their affect by causing structural alterations of the kinase leading to aggregation. Recognition of this phenomenon has important implications for the development of novel inhibitors of two-component systems and should facilitate the rapid identification and elimination of compounds with nonspecific affects from medicinal chemistry drug discovery programs. (+info)
Specific accumulation and elimination kinetics of tris(4-chlorophenyl)methane, tris(4-chlorophenyl)methanol, and other persistent organochlorines in humans from Japan.
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We examined human adipose tissue, liver, and bile from humans in Japan to understand the contamination status, specific accumulation, and elimination of two newly identified environmental contaminants, tris(4-chlorophenyl)methane (TCPMe), tris(4-chlorophenyl)methanol (TCPMOH), and other persistent organochlorines such as polychlorinated biphenyls (PCBs), DDT and its metabolites (DDTs), hexachlorocyclohexane isomers (HCHs), hexachlorobenzene (HCB), and chlordane compounds (CHLs). TCPMe and TCPMOH concentrations in Japanese human adipose tissue were slightly higher than those reported previously, indicating widespread exposure to these compounds in humans. Elevated residues of PCBs and DDTs are found in adipose tissue and liver. Concentrations in bile strongly correlated with concentrations in adipose fat and liver, which may suggest an equilibration in adipose fat/bile and liver/bile and possible biliary excretion of persistent organochlorines in humans. Composition of the organochlorines accumulated further indicates a metabolic capacity in humans higher than that of marine mammals. We observed age-dependent accumulation for TCPMe, TCPMOH, and other organochlorines, but there were no significant gender differences. p,p'-DDE and TCPMe were estimated to have low biliary excretion rate. Elimination potential of persistent organochlorines may be related to their octanol-water partition coefficient. The relationship between excretion rate and octanol-water partition coefficient may be used to predict the biliary excretion potential of some other lipophilic organochlorines such as dioxins and dibenzofurans in humans. The presence of organochlorines in bile suggests that the hepatic excretory system plays a major role in the elimination of xenobiotics in humans. To our knowledge, this is the first study of accumulation and elimination of TCPMe and TCPMOH in humans. (+info)