Waller Ross F, Ralph Stuart A, Reed Michael B, Su Vanessa, Douglas James D, Minnikin David E, Cowman Alan F, Besra Gurdyal S, McFadden Geoffrey I
School of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria 3010, Australia.
Antimicrob Agents Chemother. 2003 Jan;47(1):297-301. doi: 10.1128/AAC.47.1.297-301.2003.
It has long been held that the malaria parasite, Plasmodium sp., is incapable of de novo fatty acid synthesis. This view has recently been overturned with the emergence of data for the presence of a fatty acid biosynthetic pathway in the relict plastid of P. falciparum (known as the apicoplast). This pathway represents the type II pathway common to plant chloroplasts and bacteria but distinct from the type I pathway of animals including humans. Specific inhibitors of the type II pathway, thiolactomycin and triclosan, have been reported to target this Plasmodium pathway. Here we report further inhibitors of the plastid-based pathway that inhibit Plasmodium parasites. These include several analogues of thiolactomycin, two with sixfold-greater efficacy than thiolactomycin. We also report that parasites respond very rapidly to such inhibitors and that the greatest sensitivity is seen in ring-stage parasites. This study substantiates the importance of fatty acid synthesis for blood-stage parasite survival and shows that this pathway provides scope for the development of novel antimalarial drugs.
长期以来，人们一直认为疟原虫属的疟原虫无法进行脂肪酸的从头合成。最近，随着恶性疟原虫（称为顶质体）残留质体中存在脂肪酸生物合成途径的数据出现，这一观点被推翻。该途径代表了植物叶绿体和细菌共有的II型途径，但不同于包括人类在内的动物的I型途径。据报道，II型途径的特异性抑制剂硫内酯霉素和三氯生可作用于这种疟原虫途径。在此，我们报告了抑制疟原虫寄生虫的基于质体途径的其他抑制剂。这些包括硫内酯霉素的几种类似物，其中两种的效力比硫内酯霉素高六倍。我们还报告说，寄生虫对这类抑制剂反应非常迅速，并且在环状体期寄生虫中观察到最大的敏感性。这项研究证实了脂肪酸合成对血液期寄生虫存活的重要性，并表明该途径为新型抗疟药物的开发提供了空间。
