Chloroquine resistance and the physiology of the malaria parasite s digestive vacuole

氯喹耐药性和疟疾寄生虫消化液泡的生理学

• 批准号: nhmrc : 418055
• 负责人: Prof Kiaran Kirk
• 金额: $ 19.2万
• 依托单位: Australian National University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/chloroquine-resistance-physiology-digestive-vacuole/80754
• 关键词: Chloroquine; resistance; physiology; malaria; parasite

Malaria is an infectious disease, caused by a single-celled parasite which invades the red blood cells of its human host. Each year, malaria causes the death of up to 3 million people, mostly children under the age of 5 The parasite has become resistant to most, if not all, of the antimalarial drugs presently available, and there is no vaccine. There is therefore an urgent need to develop new antimalarial drugs, and-or to devise strategies for overcoming the parasite s drug resistance mechanisms. Chloroquine was, for many years, the mainstay of antimalarial chemotherapy and was, in many senses, a 'wonder-drug' cheap, safe and effective. However the emergence and spread of parasites that are resistant to chloroquine has meant that the drug is now largely useless as an antimalarial. Chloroquine kills (sensitive) parasite through an effect on the parasite s digestive vacuole an internal acidic compartment in which the parasite breaks down protein taken up from its host red blood cell. This compartment plays a crucial role in the growth and proliferation of the parasite. Yet we understand very little about its basic physiology, and nor do we understand the mechanism by which chloroquine-resistant parasites are able to survive exposure to the drug. The aim of the work proposed here is to gain an increased understanding of some of the mechanisms underlying the physiology of the parasite s digestive vacuole, as well as some of the factors influencing the accumulation of chloroquine within this compartment. The former part of the work may well reveal new antimalarial drug targets. The latter part of the work will increase our understanding of the mechanism of chloroquine resistance, thereby laying the groundwork for strategies by which these mechanisms might be circumvented and chloroquine-related drugs thereby restored to the front-line of our ongoing and increasingly desperate fight against malaria.

疟疾是一种传染病，由一种单细胞寄生虫侵入人体的红细胞引起。每年，疟疾导致多达300万人死亡，其中大多数是5岁以下的儿童。寄生虫已经对目前可用的大多数（如果不是全部的话）抗疟药物产生了抗药性，而且没有疫苗。因此，迫切需要开发新的抗疟药物，和/或设计克服寄生虫抗药性机制的策略。多年来，氯喹一直是抗疟化疗的主要药物，在许多意义上，它是一种便宜、安全和有效的“神奇药物”。然而，对氯喹有抗药性的寄生虫的出现和传播意味着这种药物现在基本上是无用的抗疟疾药物。氯喹通过影响寄生虫的消化泡（一种内部酸性隔室，寄生虫在其中分解从其宿主红细胞中摄取的蛋白质）来杀死（敏感的）寄生虫。这个区室在寄生虫的生长和增殖中起着至关重要的作用。然而，我们对它的基本生理学知之甚少，我们也不了解氯喹抗性寄生虫能够在暴露于药物后存活的机制。本文的目的是进一步了解寄生虫消化泡生理学的一些机制，以及影响氯喹在此隔室中积累的一些因素。前一部分工作很可能揭示新的抗疟疾药物靶点。这项工作的后半部分将增加我们对氯喹抗药性机制的了解，从而为可能绕过这些机制的战略奠定基础，从而使与氯喹有关的药物重新回到我们正在进行的和日益绝望的防治疟疾斗争的第一线。