A plastid organelle as a drug target in apicomplexan parasites
A plastid organelle as a drug target in apicomplexan parasites
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作者：
Fichera, ME;Roos, DS
顶复门的寄生虫包括许多重要的人类和兽医病原体，如疟原虫（疟疾）、弓形虫（与艾滋病和先天性神经系统先天缺陷相关的主要机会性感染）和艾美耳虫（家禽和牛的一种经济上重要的疾病）（1-4）。最近的研究已经在这些寄生虫中发现了一种不寻常的细胞器（5-7）：一种质体，似乎是通过绿藻的次生内共生获得的(7)。本研究表明，环丙沙星可以特异性地抑制弓形虫速殖子的顶质体基因组复制，这种抑制作用可以阻断寄生虫的复制。此外，寄生虫死亡的特殊动力学与暴露于克林霉素和大环内酯类抗生素后观察到的相同（8,9），这些抗生素被认为是针对顶质体中的蛋白质合成（9,10）。相反，克林霉素（及其功能相关化合物）在药物应用后立即抑制质体复制，这是迄今为止这些抗生素所描述的最早效果。我们的研究结果直接将顶质体功能与寄生虫存活联系起来，验证了这种有趣的细胞器作为杀寄生虫药物设计的有效靶点。
Parasites of the phylum Apicomplexa include many important human and veterinary pathogens such as Plasmodium (malaria), Toxoplasma (a leading opportunistic infection associated with AIDS and congenital neurological birth defects), and Eimeria (an economically significant disease of poultry and cattle)(1-4). Recent studies have identified an unusual organelle in these parasites(5-7): a plastid that appears to have been acquired by secondary endosymbiosis of a green alga(7). Here ive show that replication of the apicomplexan plastid (apicoplast) genome in Toxoplasma gondii tachyzoites can be specifically inhibited using ciprofloxacin, and that this inhibition blocks parasite replication. Moreover, parasite death occurs with peculiar kinetics that are identical to those observed after exposure to clindamycin and macrolide antibiotics(8,9), which have been proposed to target protein synthesis in the apicoplast(9,10). Conversely, clindamycin (and functionally related compounds) immediately inhibits plastid replication upon drug application-the earliest effect so far described for these antibiotics. Our results directly link apicoplast function with parasite survival, validating this intriguing organelle as an effective target for parasiticidal drug design.