Development of novel antimalarial targets and combination therapies to address drug resistance

疟疾疟原虫仍然是一个巨大的公共卫生负担。为了维持最近在降低疟疾相关发病率和死亡率方面取得的进展，需要在了解抗疟疾作用机制和耐药性方面取得进一步进展。为了实现这种高通量的单药和联合筛选技术将被用于恶性疟原虫药物反应的化学基因组学分析。然后将对这些信息进行分析，以确定不同的药物反应和潜在的候选基因位点，这些基因位点将使用最近开发的恶性疟原虫遗传工具进行进一步测试。此外，我们将进一步评估包括机制询问板（MIPE）文库在内的药物收集文库中的有效小分子，以开发抗疟疾联合治疗的先导化合物。化合物文库将针对标准实验室株系和具有不同抗性表型的株系进行筛选。这些信息将允许确定对目前使用的抗疟药具有抗药性的寄生虫仍然有效的发育候选药物。

Plasmodium malaria remains a tremendous public health burden. In order to sustain recent progress in decreasing malaria related morbidity and mortality further progress in understanding antimalarial mechanism of action and resistance is required. In order to achieve this high-throughput single agent and combination screening technology will be utilized to chemogenomic profiling of P. falciparum drug responses. This information will then be analyzed to identify differential drug responses and the underlying candidate genetic loci that will be further tested using recently developed genetic tools for P. falciparum. In addition, potent small molecules from our drug collection libraries, including the Mechanism Interrogation PlatE (MIPE) library, will be further evaluated for development of lead compounds for antimalarial combination therapies. Compound libraries will be screened against standard laboratory lines and lines with distinct resistance phenotypes. The information will permit the identification of developmental candidates that remain potent against parasites resistant to current utilized antimalarials.