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In Vivo Efficacy and Pharmacokinetics of AC98-6446, a Novel Cyclic Glycopeptide, in Experimental Infection Models. William J. Weiss, 2004.AC98-6446 is a novel semisynthetic derivative of a natural product related to the mannopeptimycins produced by Streptomyces hygroscopicus . Naturally occurring esterified mannopeptimycins exhibited excellent in vitro activity but only moderate in vivo efficacy against staphylococcal infection . The in vivo efficacy and pharmacokinetics of AC98-6446 were investigated in murine acute lethal, bacterial thigh and rat endocarditis infections . Pharmacokinetics were performed in mice, rats, monkeys, and dogs . Acute lethal infections were performed with several gram-positive isolates: Staphylococcus aureus (methicillin-susceptible and methicillin-resistant staphylococci), vancomycin-resistant Enterococcus faecalis, and penicillin-susceptible and -resistant Streptococcus pneumoniae . The 50% effective dose for all isolates tested ranged from 0.05 to 0.39 mg/kg of body weight after intravenous (i.v.) administration . Vancomycin was more than fivefold less efficacious against all of these same infections . Results of the thigh infection with S . aureus showed a static dose for AC98-6446 of 0.4 mg/kg by i.v . administration . Reduction of counts in the thigh of >2 log10 CFU were achieved with doses of 1 mg/kg . i.v . administration of 3 mg/kg twice a day for 3 days resulted in a >3 log10 reduction in bacterial counts of vancomycin-susceptible and -resistant E . faecalis in a rat endocarditis model . Pharmacokinetics of AC98-6446 showed an increase in exposure (area under the concentration-time curve) from mouse to dog species . The i.v . half-life (t1/2) increased threefold between rodents and the higher species dosed . Efficacy of AC98-6446 has been demonstrated in several models of infection with resistant gram-positive pathogens . This glycopeptide exhibited bactericidal activity in these models, resulting in efficacy at low doses with reduction in bacterial load . Topology of RbsC, the Membrane Component of the Escherichia coli Ribose Transporter. Jeffrey B. Stewart, 2003.The topology of RbsC, the membrane component of the ribose transporter in Escherichia coli, has been determined by using 34 single-cysteine mutants and a modified fluorescence labeling technique designated multiplex labeling . This technique gives topology, expression, and localization information for a membrane protein from a single batch of bacterial cells . The results indicate that RbsC contains 10 transmembrane-spanning helices, with the N and C termini being in the cytosol . This topology matches predictions from the latest prediction programs and the topology of the similar, recently crystallized membrane protein BtuC . Degradation of Benzo[a]pyrene by the Litter-Decomposing Basidiomycete Stropharia coronilla: Role of Manganese Peroxidase. Kari T. Steffen, 2003.The litter-decomposing basidiomycete Stropharia coronilla, which preferably colonizes grasslands, was found to be capable of metabolizing and mineralizing benzo[a]pyrene (BaP) in liquid culture . Manganese(II) ions (Mn2+) supplied at a concentration of 200 µM stimulated considerably both the conversion and the mineralization of BaP; the fungus metabolized and mineralized about four and twelve times, respectively, more of the BaP in the presence of supplemental Mn2+ than in the basal medium . This stimulating effect could be attributed to the ligninolytic enzyme manganese peroxidase (MnP), whose activity increased after the addition of Mn2+ . Crude and purified MnP from S . coronilla oxidized BaP efficiently in a cell-free reaction mixture (in vitro), a process which was enhanced by the surfactant Tween 80 . Thus, 100 mg of BaP liter-1 was converted in an in vitro reaction solution containing 1 U of MnP ml-1 within 24 h . A clear indication was found that BaP-1,6-quinone was formed as a transient metabolite, which disappeared over the further course of the reaction . The treatment of a mixture of 16 different polycyclic aromatic hydrocarbons (PAHs) selected by the U.S . Environmental Protection Agency as model standards for PAH analysis (total concentration, 320 mg liter-1) with MnP resulted in concentration decreases of 10 to 100% for the individual compounds, and again the stimulating effect of Tween 80 was observed . Probably due to their lower ionization potentials, poorly bioavailable, high-molecular-mass PAHs such as BaP, benzo(g,h,i)perylene, and indeno(1,2,3-c,d)pyrene were converted to larger extents than low-molecular-mass ones (e.g., phenanthrene and fluoranthene) .
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