TRITIUM LABELLING OF GEMFIBROZIL: ANTIBIOTICS & KILLING INTRACELLULAR BACTERIA

点击翻译按钮获取中文摘要

Bacteria that grow inside cells, such as Legionella, Mycobacteria, Salmonella, and Listeria are hard to kill with certain antibiotics. Dr. Samuel Silverstein's laboratory may have a way to overcome the problem, using the cholesterol-lowering drug, gemfibrozil. Silverstein's group identified that gemfibrozil prevents the efflux of fluoroquinolone, an antibiotic, from infected cells, thereby increasing both the intracellular antibiotic concentration and the concentration of antibiotic to which the bacteria are exposed. Normally the antibiotic, which is an organic anion, gets ejected from the cell via an organic anion transporter. Because gemfibrozil blocks the transporter from ferrying the antibiotics out of the cell, the antibiotic then becomes available to kill the intracellular bacteria. (Journal of Experimental Medicine, 176, 1439 (1992)). His laboratory is in the process of identifying the transporter that carries the organic anion antibiotic. Its activity is found in mouse macrophage cell lines, mouse macrophage primary cultures, and primary human cultured monocytes that differentiate into macrophages. Studies of the use of other anionic antibiotics in bacterially infected mice are under way. Dr. Silverstein recently won a Guggenheim Award to study this anion transporter. A radioactive form of gemfibrozil was required to further this research. The base molecule was brominated by the action of bromine in the presence of acetic acid and sodium acetate. The brominated compound was dehalogenated to yield tritiated gemfibrozil of very high purity and specific activity, as shown by HPLC and NMR analyses.