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

摘要 疟疾的治疗和控制受到抗药性的严重挑战。具有广泛的抵抗 对于较老的药物，以青蒿素为基础的联合疗法(ACTs)是抗疟疾治疗的支柱， 但ACT的疗效因对青蒿素和伙伴药物的耐药性而受到威胁。新的抗疟疾药物是 需要的。由疟疾药物风险投资(MMV)带头，一个强大的新抗疟疾先导渠道 化合物正在开发中。然而，对新的抗疟疾药物的耐药性是可以预见的。在一个 已经确定了药物靶标和耐药机制的病例数量，但研究重点放在 少量恶性疟原虫实验室菌株。考虑到对先导抗疟疾药物的敏感性也是至关重要的 新鲜的恶性疟原虫野外分离株，特别是来自非洲的分离株。在试点研究中，我们发现了重要的 乌干达恶性疟原虫新鲜分离株对先导抗疟疾化合物体外敏感性的变异性。在……里面 在某些情况下，这种变异性似乎与实验室中发现的抗药性机制有关，但 以前在野外隔离中没有见过。对减少的程度和机制有更好的了解 非洲野毒株的敏感性将对指导下一代病毒的最佳发展具有重要价值 联合抗疟疾疗法。该项目将建立在我们集团和 MMV提供了来自乌干达的试点数据，以及布基纳法索的另一个长期合作。我们的 该计划将提供最先进的体外恶性疟原虫敏感性评估，这些敏感性与基因和 田间样品的表型特征。我们推测恶性疟原虫分离自乌干达， 布基纳法索将对含铅抗疟疾化合物表现出不同的敏感性， 田间分离株的基因类型和表型将确定共同的抗性机制和最佳 综合疗法。我们的具体目标将是：(1)表征体外对先导抗疟疾药物的敏感性 恶性疟原虫野外分离株化合物的研究(2)鉴定药敏异常值的基因型别 野外分离株中敏感性降低的介体，以及(3)表征药物敏感性的表型 异常值，以阐明铅抗疟疾化合物的抗药性机制。我们的研究将定义 作为抗疟疾药物和INFO的最重要的正在开发的新化合物的耐药性机制 最佳抗疟疾药物组合的选择和继续药物发现工作的方向。

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.