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<p>New antimalarial drugs are needed to combat the current emergence and spread of <i>Plasmodium falciparum</i> parasite resistance to artemisinin-based combination therapies. Here, we characterize ZY19489, a triaminopyrimidine presently in a Phase Ib clinical trial. Asexual blood-stage parasites pressured with ZY19489 acquire low-grade resistance, mediated by a novel mutation in the <i>P. falciparum</i> chloroquine resistance transporter (PfCRT) that causes slow growth rates and a substantial fitness cost. ZY19489-resistant parasites lose their chloroquine resistance status and become hypersusceptible to piperaquine&#xa0;(PPQ), an artemisinin-based combination partner drug. Uptake studies in proteoliposomes loaded with drug-resistant PfCRT isoforms demonstrate that ZY19489 can block mutant PfCRT-mediated PPQ and chloroquine transport. In parasites, PfCRT mutant variants can mediate PPQ and chloroquine resistance via their efflux out of the digestive vacuole. Our findings evoke a scenario of an evolutionary trap whereby resistance to ZY19489 can block PPQ and chloroquine efflux and thereby restore their activity. Metabolomic studies show that ZY19489 leads to significantly reduced intracellular levels of short hemoglobin-derived peptides (a natural substrate of PfCRT) and accumulation of pyrimidine deoxynucleotides. Our results present a possible marker for tracking the evolution of clinical resistance to ZY19489 and a rationale for pairing this molecule with PPQ to generate a resistance-refractory combination.</p>

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Collateral hypersensitivity between ZY19489 and piperaquine neutralizes PfCRT-mediated drug efflux and Plasmodium falciparum resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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  • John Okombo,
  • Tolla Ndiaye,
  • Tarrick Qahash,
  • Igor M. R. Moura,
  • Eva Gil-Iturbe,
  • Laura M. Hagenah,
  • Jessica L. Bridgford,
  • Vinicius Bonatto,
  • Kurt E. Ward,
  • Tomas Yeo,
  • Sunil K. Narwal,
  • Lily V. Orta,
  • Isla Anderson,
  • Satish K. Dhingra,
  • Charisse Flerida A. Pasaje,
  • Heekuk Park,
  • Jonathan Kim,
  • Rafael V. C. Guido,
  • Maria Belén Jiménez-Diaz,
  • Iñigo Angulo-Barturen,
  • Jacquin C. Niles,
  • Filippo Mancia,
  • Anne-Catrin Uhlemann,
  • Sachel Mok,
  • Matthias Quick,
  • Elizabeth A. Winzeler,
  • Didier Leroy,
  • Manuel Llinás,
  • Vandana Thathy,
  • David A. Fidock

摘要

New antimalarial drugs are needed to combat the current emergence and spread of Plasmodium falciparum parasite resistance to artemisinin-based combination therapies. Here, we characterize ZY19489, a triaminopyrimidine presently in a Phase Ib clinical trial. Asexual blood-stage parasites pressured with ZY19489 acquire low-grade resistance, mediated by a novel mutation in the P. falciparum chloroquine resistance transporter (PfCRT) that causes slow growth rates and a substantial fitness cost. ZY19489-resistant parasites lose their chloroquine resistance status and become hypersusceptible to piperaquine (PPQ), an artemisinin-based combination partner drug. Uptake studies in proteoliposomes loaded with drug-resistant PfCRT isoforms demonstrate that ZY19489 can block mutant PfCRT-mediated PPQ and chloroquine transport. In parasites, PfCRT mutant variants can mediate PPQ and chloroquine resistance via their efflux out of the digestive vacuole. Our findings evoke a scenario of an evolutionary trap whereby resistance to ZY19489 can block PPQ and chloroquine efflux and thereby restore their activity. Metabolomic studies show that ZY19489 leads to significantly reduced intracellular levels of short hemoglobin-derived peptides (a natural substrate of PfCRT) and accumulation of pyrimidine deoxynucleotides. Our results present a possible marker for tracking the evolution of clinical resistance to ZY19489 and a rationale for pairing this molecule with PPQ to generate a resistance-refractory combination.