ORGANELLE GENOMES OF MALARIAL PARASITES

显然需要有目标不同于受外地广泛耐药药物影响的药物的现有抗疟疾药物。由于线粒体在真核生物中扮演的关键角色，它们可以形成这样的靶标。挑战是找到在不影响寄主线粒体的情况下影响寄生虫线粒体生理的化合物。我们之前确定了疟疾寄生虫线粒体遗传学和生物化学的几个方面，这些方面可能会以选择性的方式受到影响。阿托瓦酮是一种新开发的广谱抗寄生虫药物，它选择性地抑制疟疾线粒体的电子传递，并显示出跨寄生虫内线粒体膜的电位崩溃。阿托瓦酮作为单一药物会导致不可接受的治疗失败，需要加入增效药物普罗瓜尼。我们的研究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一个潜在的解释。为了继续我们的研究，我们提出了一些实验，这些实验将扩大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产生更详细的看法。我们将利用我们实验室开发的遗传和生化工具来研究药物作用和耐药的机制。疟疾基因组计划正在迅速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，将识别核编码的线粒体基因，并确定它们的表达模式。为了开发研究疟疾寄生虫线粒体生理学的工具，将使用遗传学方法来识别将核编码蛋白定向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检验很有价值。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。阿托瓦酮的问世为抗寄生虫药物选择性靶向寄生虫线粒体的研究奠定了基础。我们提议的研究将获得对药物作用的更好的机械性见解，以帮助未来的药物开发战略。拟议的研究还将提供有关寄生虫线粒体功能的基本信息，希望这些也可以成为开发其他有效的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.