Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs
Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs
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DOI：
10.1126/science.285.5433.1573
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发表时间：
1999-09-03
期刊：
影响因子：
56.9
通讯作者：
Beck, E
中科院分区：
文献类型：
--
作者：
Jomaa, H;Wiesner, J;Beck, E
恶性疟原虫中存在的不依赖于甲羟戊酸的类异戊二烯生物合成途径被证明是疟疾化疗的有效靶点。该途径包括 1-脱氧-D-木酮糖 5-磷酸 (DOXP) 作为关键代谢物。编码 DOXP 合酶和 DOXP 还原异构酶的两个基因的存在表明，恶性疟原虫中的类异戊二烯生物合成依赖于 DOXP 途径。该途径可能位于顶质体中。重组恶性疟原虫 DOXP 还原异构酶被福米霉素及其衍生物 FR-900098 抑制。这两种药物都能抑制多重耐药恶性疟原虫菌株的体外生长。用这些药物治疗后，感染啮齿动物疟原虫温氏疟原虫的小鼠被治愈。
A mevalonate-independent pathway of isoprenoid biosynthesis present in Plasmodium falciparum was shown to represent an effective target for chemotherapy of malaria. This pathway includes 1-deoxy-D-xylulose 5-phosphate (DOXP) as a key metabolite. The presence of two genes encoding the enzymes DOXP synthase and DOXP reductoisomerase suggests that isoprenoid biosynthesis in P. falciparum depends on the DOXP pathway. This pathway is probably Located in the apicoplast. The recombinant P, falciparum DOXP reductoisomerase was inhibited by fosmidomycin and its derivative, FR-900098. Both drugs suppressed the in vitro growth of multidrug-resistant P. falciparum strains. After therapy with these drugs, mice infected with the rodent malaria parasite P. vinckei were cured.