A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants.

IF 5.5 1区 医学 Q1 MICROBIOLOGY PLoS Pathogens Pub Date : 2024-10-29 eCollection Date: 2024-10-01 DOI:10.1371/journal.ppat.1012627
Letícia Tiburcio Ferreira, Gustavo Capatti Cassiano, Luis Carlos Salazar Alvarez, John Okombo, Juliana Calit, Diana Fontinha, Eva Gil-Iturbe, Rachael Coyle, Carolina Horta Andrade, Per Sunnerhagen, Daniel Youssef Bargieri, Miguel Prudêncio, Matthias Quick, Pedro V Cravo, Marcus C S Lee, David A Fidock, Fabio Trindade Maranhão Costa
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Abstract

Artemisinin-based combination therapy (ACT) is the mainstay of effective treatment of Plasmodium falciparum malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs. In this study, we characterized the asexual blood stage antiplasmodial activity and resistance mechanisms of LDT-623, a 4-aminoquinoline (4-AQ). We also detected LDT-623 activity against multiple stages (liver schizonts, stage IV-V gametocytes, and ookinetes) of Plasmodium's life cycle, a feature unlike other 4-AQs such as chloroquine (CQ) and piperaquine (PPQ). Using heme fractionation profiling and drug uptake studies in PfCRT-containing proteoliposomes, we observed inhibition of hemozoin formation and PfCRT-mediated transport, which constitute characteristic features of 4-AQs' MoA. We also found minimal cross-resistance to LDT-623 in a panel of mutant pfcrt or pfmdr1 lines, but not the PfCRT F145I mutant that is highly resistant to PPQ resistance yet is very unfit. No P. falciparum parasites were recovered in an in vitro resistance selection study, suggesting a high barrier for resistance to emerge. Finally, a competitive growth assay comprising >50 barcoded parasite lines with mutated resistance mediators or major drug targets found no evidence of cross-resistance. Our findings support further exploration of this promising 4-AQ.

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一种新型 4-氨基喹啉化学型,具有多级抗疟活性,且与 PfCRT 和 PfMDR1 突变体无交叉抗药性。
青蒿素类复方疗法(ACT)是有效治疗恶性疟原虫疟疾的主要手段。然而,东南亚地区广泛存在的部分青蒿素抗药性以及最近在东非部分地区出现的抗药性危及了青蒿素综合疗法的长期效用。这突出表明,有必要找出具有新作用模式(MoAs)的化学型,以规避对青蒿素综合疗法的抗药性。在这项研究中,我们对 4-氨基喹啉(4-AQ)LDT-623 的无性血期抗疟活性和抗药性机制进行了鉴定。我们还检测到 LDT-623 对疟原虫生命周期的多个阶段(肝裂殖子、IV-V 期配子细胞和卵母细胞)都有活性,这与氯喹(CQ)和哌喹(PPQ)等其他 4-AQ 不同。通过对含 PfCRT 蛋白脂质体进行血红素分馏分析和药物吸收研究,我们观察到了对血色素形成和 PfCRT 介导的转运的抑制作用,这构成了 4-AQs MoA 的特征。我们还在一组突变的 pfcrt 或 pfmdr1 株系中发现了对 LDT-623 的最小交叉抗性,但没有发现对 PPQ 抗性高度耐受但非常不适合的 PfCRT F145I 突变体。在体外抗药性选择研究中,没有发现恶性疟原虫寄生虫,这表明抗药性出现的门槛很高。最后,由超过 50 个条码寄生虫品系组成的竞争性生长试验发现,抗药性介质或主要药物靶标发生变异的寄生虫品系没有交叉抗药性的迹象。我们的研究结果支持进一步探索这种前景广阔的 4-AQ。
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来源期刊
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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