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

总结 疟疾的治疗和控制受到抗药性的严重挑战。由于普遍的抵抗 对于较老的药物，青蒿素类复方疗法是抗疟治疗的主要手段， 但青蒿素类药物及其伙伴药物的耐药性威胁着青蒿素综合疗法的疗效。新的抗疟疾药物是 needed.由疟疾新药研发公司（MMV）牵头，这是一个强大的新型领先抗疟药管道。 化合物正在开发中。但是，可以预期对新的抗疟药会产生抗药性。中 许多病例的药物靶点和耐药机制已经确定，但研究的重点是 少量的恶性疟原虫实验室菌株。同样重要的是要考虑对铅抗疟药的敏感性， 新鲜的恶性疟原虫田间分离株，特别是来自非洲的分离株。在试点研究中，我们已经确定了重要的 新鲜乌干达恶性疟原虫分离株对铅抗疟化合物体外敏感性的变异性。在 在某些情况下，这种变异性似乎与实验室确定的耐药机制有关， 以前在田间分离株中未发现。更好地了解减少的程度和机制 非洲田间分离株的敏感性将对下一代的最佳开发具有重要价值 联合抗疟疗法。该项目将建立在我们集团和 MMV提供了来自乌干达的试验数据，另一个长期合作伙伴是布基纳法索。我们 该计划将提供最先进的评估离体恶性疟原虫敏感性与基因型和 田间样品的表型表征。我们假设恶性疟原虫从乌干达分离， 布基纳法索将展示对主要抗疟化合物的不同敏感性， 田间分离物的基因型和表型将确定共同的抗性机制和最佳的 联合治疗我们的具体目标将是：（1）表征体外敏感性铅抗疟药 恶性疟原虫田间分离株的化合物，（2）表征药物敏感性离群值的基因型，以识别 介导的敏感性降低，在外地分离，和（3）表征表型的药物敏感性 离群值，以阐明铅抗疟化合物的耐药性机制。我们的研究将定义 正在开发的最重要的新化合物作为抗疟药的耐药机制， 最佳抗疟药物组合的选择和继续药物发现努力的方向。

Summary The treatment and control of malaria are seriously challenged by drug resistance. With widespread resistance to older agents, artemisinin-based combination therapies (ACTs) are the mainstay for antimalarial treatment, but ACT 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 antimalarial 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. In pilot studies we have identified important variability in ex vivo sensitivity of fresh Ugandan P. falciparum isolates to lead antimalarial compounds. In some cases this variability appears to be linked to mechanisms of resistance identified in the laboratory, but not previously seen in field isolates. A better understanding of the extent of and mechanisms of decreased sensitivity in African field isolates will be of great value in informing optimal development of next-generation combination antimalarial therapies. This project will build on an ongoing collaboration between our group and MMV, which has provided pilot data from Uganda, and another longstanding collaboration in Burkina Faso. Our program will offer state-of-the-art assessment of ex vivo P. falciparum sensitivities linked to genotypic and phenotypic characterization of field samples. We hypothesize that P. falciparum isolates from Uganda and Burkina Faso will demonstrate varied sensitivity to lead antimalarial compounds, and that characterization of genotypes and phenotypes of field isolates will identify shared resistance mechanisms and optimal combination therapies. Our specific aims will be: (1) to characterize ex vivo sensitivity to lead antimalarial compounds of P. falciparum field isolates, (2) to characterize genotypes of drug sensitivity outliers to identify mediators of decreased sensitivity in field isolates, 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.