ORGANELLE GENOMES OF MALARIAL PARASITES

很明显，需要有目标不同于在疟疾领域广泛存在耐药性的药物的抗疟疾药物。由于线粒体在真核生物中所起的关键作用，它们可以形成这样的靶标。挑战在于找到既能影响寄生虫线粒体生理又不影响宿主线粒体的化合物。我们之前确定了疟疾寄生虫的线粒体遗传学和生物化学的几个方面，这些方面可能以选择性的方式受到影响。阿托伐醌是一种新开发的广谱抗寄生虫药物，选择性地抑制疟原虫线粒体中的电子传递，并显示在疟原虫内线粒体膜上破坏电势。阿托伐酮作为单一药物导致不可接受的治疗失败，需要包括协同药物，普罗胍。我们的调查为这种协同作用的机制提供了线索，并为相对缺乏耐药性的出现提供了可能的解释。为了继续我们的研究，我们提出了一些实验，这些实验将扩展对抗线粒体药物作用和耐药性的理解，并对疟疾寄生虫的线粒体生理学有更详细的了解。药物作用和耐药性的机制将利用我们实验室开发的遗传和生化工具进行研究。疟疾基因组计划正迅速接近完成恶性疟原虫的整个DNA序列，为了利用这些信息进一步了解寄生虫的线粒体生理学，将鉴定核编码的线粒体基因并确定其表达模式。为了开发用于研究疟疾寄生虫线粒体生理学的工具，将使用遗传方法来识别将核编码蛋白引导到疟疾线粒体的信号序列。这些工具将对疟疾寄生虫线粒体功能假说的实验测试有价值。在夏季，提出了一种综合的方法来发展疟疾寄生虫线粒体生理学的机制和功能观点。随着阿托伐醌的出现，抗寄生虫药物选择性靶向寄生虫线粒体的途径得以建立。我们提出的研究将为药物作用提供更好的机制见解，以帮助未来的药物开发策略。提出的研究还将提供关于寄生虫线粒体功能的基本信息，希望这些信息也可以成为开发其他有效疟疾治疗手段的基础。

There is a clear need to have available anti-malarial drugs with targets different from those affected by agents for which resistance is widespread in the field. Because of the critical role played by mitochondria in eukaryotic organisms, they could form such targets. The challenge is to find compounds that affect the parasite mitochondrial physiology without affecting the host mitochondria. We previously identified several aspects of mitochondrial genetics and biochemistry of malaria parasites that could potentially be affected in a selective manner. Atovaquone, a newly developed broad-spectrum anti-parasite drug, selectively inhibits electron transport in malarial mitochondria, and was shown to collapse electropotential across the inner mitochondrial membrane in the parasites. Atovaquone as a single agent leads to unacceptable level of treatment failure, requiring the inclusion of synergistic drug, proguanil. Our investigations have provided clues as to the mechanism for this synergy, and a potential explanation for the relative lack of resistance emergence. To continue our investigations, we propose experiments that will extend the understanding of anti-mitochondrial drug action and resistance, and derive a more detailed view of mitochondrial physiology in malaria parasites. Mechanisms of drug action and resistance will be investigated by using genetic and biochemical tools that have been developed in our laboratory. The Malaria Genome Project is fast approaching completion of the entire DNA sequence of Plasmodium falciparum, and to use this information for further insights into mitochondrial physiology of the parasites, nuclearly encoded mitochondrial genes will be identified and their expression patterns will be determined. To develop tools for studying mitochondrial physiology in malaria parasites, genetic approaches will be used to identify signal sequences that direct nuclearly encoded proteins to the malarial mitochondria. These tools will be valuable for experimental testing of hypotheses regarding mitochondrial functions in malaria parasites. In summer, an integrated approach is proposed to develop a mechanistic and functional view of mitochondrial physiology of malaria parasites.. The approach of selective targeting parasite mitochondrion by anti-parasitic drugs has been established by the advent of atovaquone. Our proposed studies will derive better mechanistic insights into drug action to help future drug development strategies. The studies proposed will also provide basic information on parasite mitochondrial functions with a hope that these too can form the basis from which other effective means for malaria treatment can be developed.