Mechanisms of varied sensitivity of P. falciparum field isolates to the antimalarial drug pipeline

项目摘要 随着疟疾寄生虫对旧药物的广泛抗药性，基于青蒿素的联合疗法 是抗疟疾治疗的中流砥柱，但对青蒿素及其合作伙伴的抗药性威胁着疗效 毒品。需要新的抗疟疾药物。由疟疾药物风险投资公司(MMV)带头的 新的抗疟疾铅化合物的强大管道正在开发中。然而，对新制剂的抗药性 可以预料到的。在一些病例中，已经确定了药物靶点和耐药机制，但 研究集中在少量的恶性疟原虫实验室菌株上。同样重要的是要考虑到 新鲜恶性疟原虫野外分离株，特别是来自非洲的分离株对铅抗疟药的敏感性。有了这些 数据、基因类型和额外的表型分析可以识别不同的 敏感性，正如我们到目前为止对多种化合物的描述，告知下一步的最佳发展- 世代联合抗疟药。本申请寻求继续资助一个项目，该项目的特点是 乌干达和布基纳法索分离的疟疾寄生虫对抗疟疾药物的敏感性 发展。我们提供了对体外恶性疟原虫易感性的最先进的评估，这些易感性与高 通过基因分型来提高我们对药物作用机制和 抵抗。根据迄今产生的数据支持，我们假设非洲恶性疟原虫分离株将 对先导抗疟疾化合物表现出不同敏感性，以及基因类型和特征 田间菌株的表型将确定共同的抗性机制，并指导选择最佳的 综合疗法。这些结果将对我们开发下一代组合具有重要价值 抗疟疾药物，并继续努力发现更多的新化合物。我们的具体目标是： (1)表征恶性疟原虫野外分离株对先导抗疟疾化合物的体外敏感性，(2) 鉴定基因类型以确定现场分离株对抗疟疾药物敏感性降低的介体 化合物，以及(3)表征药物敏感性异常值的表型，以阐明其机制。 铅抗疟疾化合物的抗药性。我们的研究将确定大多数人的抗性机制 作为抗疟疾药物正在开发的重要新化合物，并为最佳抗疟疾药物的选择提供信息 药物组合和持续药物发现努力的方向。

Project Summary With widespread resistance of malaria parasites to older agents, artemisinin-based combination therapies are the mainstay for antimalarial treatment, but efficacy is threatened by resistance to artemisinins and partner drugs. New antimalarial drugs are needed. Spearheaded by the Medicines for Malaria Venture (MMV), a robust pipeline of new lead antimalarial compounds is under development. However, resistance to new agents can be anticipated. In a number of cases drug targets and resistance mechanisms have been identified, but studies have focused on small numbers of P. falciparum laboratory strains. It is critical also to consider sensitivity to lead antimalarials of fresh P. falciparum field isolates, especially isolates from Africa. With these data, genotypic and additional phenotypic analysis can allow identification of mechanisms underlying varied susceptibility, as we have described for multiple compounds to date, informing optimal development of next- generation combination antimalarials. This application seeks continued funding for a project characterizing susceptibilities of malaria parasites isolated in Uganda and Burkina Faso to lead antimalarials under development. We offer state-of-the-art assessment of ex vivo P. falciparum susceptibilities linked to high throughput genotypic characterization to improve our understanding of mechanisms of drug action and resistance. As supported by data generated to date, we hypothesize that African P. falciparum isolates will demonstrate varied sensitivity to lead antimalarial compounds, and that characterization of genotypes and phenotypes of field isolates will identify shared resistance mechanisms and guide selection of optimal combination therapies. These results will be of great value as we develop next-generation combination antimalarials and continue efforts toward discovery of additional novel compounds. Our specific aims will be: (1) to characterize ex vivo susceptibilities to lead antimalarial compounds of P. falciparum field isolates, (2) to characterize genotypes to identify mediators of decreased susceptibility in field isolates to lead antimalarial compounds, and (3) to characterize phenotypes of drug sensitivity outliers to elucidate mechanisms of resistance of lead antimalarial compounds. Our studies will define resistance mechanisms for the most important new compounds under development as antimalarials and inform choices of optimal antimalarial drug combinations and the direction of continued drug discovery efforts.