TRITIUM LABELLING OF GEMFIBROZIL: ANTIBIOTICS & KILLING INTRACELLULAR BACTERIA

在细胞内生长的细菌，如军团菌，分枝杆菌， 沙门氏菌和李斯特菌很难用某些抗生素杀死。 博士塞缪尔·西尔弗斯坦的实验室可能有办法克服 问题，使用降胆固醇药物吉非贝齐。 Silverstein的研究小组发现吉非罗齐可以阻止 氟喹诺酮，一种抗生素，从感染的细胞，从而 增加细胞内抗生素浓度和 抗生素的浓度是细菌所暴露的浓度。 通常抗生素是一种有机阴离子 通过有机阴离子转运体进入细胞。 因为吉非罗齐阻断了 将抗生素运送出细胞， 然后抗生素可用于杀死细胞内的细菌。 （Journal of Experimental Medicine，176，1439（1992））。 他的实验室 正在确认携带 有机阴离子抗生素 其活性在小鼠巨噬细胞中发现 细胞系、小鼠巨噬细胞原代培养物和原代人 培养的单核细胞分化成巨噬细胞。 研究 在细菌感染的小鼠中使用其它阴离子抗生素 正在进行中。 西尔弗斯坦博士最近获得了古根海姆奖， 这个阴离子转运体。 一种放射性形式的吉非罗齐， 需要进一步研究。 基础分子被溴化 在乙酸和钠存在下溴的作用 醋酸 溴化化合物被脱卤以产生氚化产物。 极高纯度和比活性的吉非罗齐，如 HPLC和NMR分析。

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.