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

疟原虫疟疾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，需要在了解抗疟作用机制和抗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，将利用化学基因组学分析恶性疟原虫的药物反应。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遗传基因座，这些基因座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，将进一步评估来自我们的药物收集库（包括机制询问平台（MIPE）库）的有效小分子，以开发用于抗疟联合疗法的先导化合物。将针对标准实验室品系和具有不同抗性表型的品系筛选化合物文库。这些信息将有助于确定对目前使用的抗疟药物具有耐药性的寄生虫仍然有效的开发候选药物。

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.