Resistance of Malaria Parasites to Artemisinin-Based Combination Therapies

标题：疟疾寄生虫对青蒿素类复方制剂的耐药性 疗法 项目摘要 非洲的疟疾防治工作面临日益严重的抗药性挑战。新青蒿素- 基于联合治疗（ACT）的方案通常非常有效， 几乎所有非洲国家都将其作为治疗单纯性疟疾的标准疗法。 然而，大量和重复使用青蒿素综合疗法，如现在发生的，将导致强烈的选择性， 对这些治疗方案的组成部分产生耐药性的压力。我们对生物学机制的理解 对青蒿素综合疗法的耐药性不完全。我们建议鉴定抗药性的最好方法- 在突变传播之前进行调解，将是评估即将出现的寄生虫 在治疗后，当他们处于长效ACT伴侣药物的选择性压力下时。我们 假设治疗失败和治疗后不久出现新感染 与青蒿素类化合物联合使用，将与疟疾寄生虫中已知和未知的突变有关， 对青蒿素伙伴药物的反应。为了验证这一假设，我们将系统地评估 最近和正在进行的临床试验在乌干达和布基纳法索，以确定寄生虫 候选突变与ACT临床反应之间的关联。我们进一步 假设青蒿素综合疗法使用增加将选择药物减少的寄生虫 敏感性，但也降低了健身。为了验证这一假设，我们将寻找 治疗结果与体外药物敏感性和适应性之间的关系。我们还将 研究引入突变的寄生虫，以测试这些改变对体外 药物敏感性和适应性的测量。我们的具体目标将是（1）确定基因型 与非洲对青蒿素综合疗法的反应减少有关，（2）评估分子机制 和对青蒿素综合疗法抗药性增加的寄生虫学后果，以及（3）描述 寄生虫多态性对药物敏感性和适应性的特定影响。我们的研究将提供 对最重要的新抗疟药的耐药性机制的重要见解 养生法他们也将有直接的实际意义，因为他们将确定分子标记 对关键疗法的耐药性，通过研究提供耐药性的“预警系统”， 基因型的寄生虫出现后不久，治疗，并提供深入了解健身 增加阻力的后果。

Title: RESISTANCE OF MALARIA PARASITES TO ARTEMISININ-BASED COMBINATION THERAPIES Project summary The control of malaria in Africa is challenged by increasing drug resistance. New artemisinin- based combination therapy (ACT) regimens are generally very effective, and have recently been adopted as standard therapy for uncomplicated malaria by nearly every country in Africa. However, heavy and repeated use of ACTs, as is now occuring, will lead to strong selective pressure for resistance to components of these regimens. Our understanding of mechanisms of resistance to ACTs is incomplete. We suggest that the best means of identifying resistance- mediating mutations before they are widespread will be to evaluate parasites that emerge soon after therapy, while they are under the selective pressure of long-acting ACT partner drugs. We hypothesize that treatment failures and the emergence of new infections soon after treatment with ACTs will be associated with known and unknown mutations in malaria parasites that alter responses to artemisinin partner drugs. To test this hypothesis, we will systematically evaluate parasites from recent and ongoing clinical trials in Uganda and Burkina Faso to identify associations between candidate mutations and clinical responses to ACTs. We further hypothesize that increasing use of ACTs will select for parasites with decreasing drug sensitivity, but also decreased fitness. To test this hypothesis, we will search for associations between treatment outcomes and in vitro measures of drug sensitivity and fitness. We will also study parasites with introduced mutations to test the impact of these alterations on in vitro measures of drug sensitivity and fitness. Our specific aims will be (1) to identify genotypes associated with decreased responses to ACTs in Africa, (2) to assess molecular mechanisms and parasitological consequences of increasing resistance to ACTs, and (3) to characterize the specific impacts of parasite polymorphisms on drug sensitivity and fitness. Our studies will offer important insights into mechanisms of resistance to the most important new antimalarial regimens. They will also have direct practical relevance, as they will identify molecular markers of resistance to key regimens, offer an "early warning system" for resistance by studying genotypes of parasites that emerge soon after treatment, and provide insight into the fitness consequences of increasing resistance.