Ramya T N C, Mishra Satyendra, Karmodiya Krishanpal, Surolia Namita, Surolia Avadhesha
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
Antimicrob Agents Chemother. 2007 Jan;51(1):307-16. doi: 10.1128/AAC.00808-06. Epub 2006 Oct 23.
Targeting of apicoplast replication and protein synthesis in the apicomplexan Toxoplasma gondii has conventionally been associated with the typical "delayed death" phenotype, characterized by the death of parasites only in the generation following drug intervention. We demonstrate that antibiotics like clindamycin, chloramphenicol, and tetracycline, inhibitors of prokaryotic protein synthesis, invoke the delayed death phenotype in Plasmodium falciparum, too, as evident from a specific reduction of apicoplast genome copy number. Interestingly, however, molecules like triclosan, cerulenin, fops, and NAS-91, inhibitors of the recently discovered fatty acid synthesis pathway, and succinyl acetone, an inhibitor of heme biosynthesis that operates in the apicoplast of the parasite, display rapid and striking parasiticidal effects. Our results draw a clear distinction between apicoplast functions per se and the apicoplast as the site of metabolic pathways, which are required for parasite survival, and thus subserve the development of novel antimalarial therapy.
针对顶复门寄生虫刚地弓形虫的顶质体复制和蛋白质合成，传统上一直与典型的“延迟死亡”表型相关，其特征是寄生虫仅在药物干预后的下一代死亡。我们证明，像克林霉素、氯霉素和四环素这样的抗生素，作为原核生物蛋白质合成的抑制剂，在恶性疟原虫中也会引发延迟死亡表型，这从顶质体基因组拷贝数的特异性减少中可以明显看出。然而，有趣的是，像三氯生、铜绿菌素、氟苯丙氨酸和NAS - 91这样的分子，作为最近发现的脂肪酸合成途径的抑制剂，以及琥珀酰丙酮，一种在寄生虫顶质体中起作用的血红素生物合成抑制剂，显示出快速且显著的杀寄生虫作用。我们的结果明确区分了顶质体本身的功能和作为寄生虫生存所需代谢途径位点的顶质体，从而有助于新型抗疟疗法的开发。
