ABSTRACT
Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated monosulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure-activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/drug therapy , Monobactams/chemistry , Monobactams/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Animals , Anti-Bacterial Agents/blood , Anti-Bacterial Agents/therapeutic use , Drug Discovery , Escherichia coli/drug effects , Escherichia coli Infections/drug therapy , Humans , Klebsiella Infections/drug therapy , Klebsiella pneumoniae/drug effects , Male , Mice , Microbial Sensitivity Tests , Monobactams/blood , Monobactams/therapeutic use , Pyridones/blood , Pyridones/chemistry , Pyridones/pharmacology , Pyridones/therapeutic use , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiazoles/blood , Thiazoles/therapeutic useABSTRACT
In this paper, an estimation method of gross beta activity from radionuclide concentrations in river water based on decay data was presented by introducing a concept of gross beta conversion factor. With the factors, the gross beta activities of some downstream water intakes and the locations downstream 1 km away from a planning nuclear power plant in inland China were estimated. The results indicated that the gross beta activities in the receiving river water due to the liquid effluent discharge of the nuclear power plant with 4 CPR 1,000 units during normal operation are lower than the recommended guideline level of 1 Bq L from the legal standard on these sites.
Subject(s)
Algorithms , Models, Chemical , Nuclear Power Plants , Radiation Monitoring/methods , Radioactive Waste/analysis , Rivers/chemistry , Water Pollutants, Radioactive/analysis , Water Pollutants, Radioactive/chemistry , Beta Particles , China , Computer Simulation , Radiation DosageABSTRACT
In this paper, the monthly gross beta activities in aerosol during 1995-2004 at Daya Bay area are reported. The gross beta activities were observed to vary in the range of 0.22-5.14 mBq m(-3) with an arithmetic average of 1.60+/-1.00 mBq m(-3) and a geometric average about 1.78+/-0.33 mBq m(-3). It is shown an obvious seasonal variation characteristic, which is ascribed to the washout mechanism and the radon-suppressing mechanism from the soil by the seasonal rainfall. The exponential attenuation with the rainfall is verified and an attenuation index is defined, which is deduced as 0.007+/-0.002 mm(-1) by regression analysis. Finally, the correlation between gross beta activities and (210)Pb concentrations is analyzed. It is indicated that the radionuclide (210)Pb contributes about 61+/-9% to the gross beta activities in the aerosol.
