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

ZY19489, a triaminopyrimidine antimalarial currently in Phase IIb trials, faces low-grade resistance in Plasmodium falciparum due to a novel mutation in the chloroquine resistance transporter PfCRT. This mutation significantly reduces parasite growth and imposes a fitness cost, while paradoxically reversing chloroquine resistance and making parasites hypersusceptible to piperaquine. Mechanistically, ZY19489 interferes with hemoglobin catabolism and blocks PfCRT-mediated efflux of piperaquine and chloroquine, creating an "evolutionary trap" that restores susceptibility to these drugs. Metabolomic analysis shows ZY19489 lowers hemoglobin-derived peptides and increases pyrimidine deoxynucleotide accumulation. These findings provide a molecular marker for monitoring resistance and support combining ZY19489 with piperaquine to form a robust, resistance-refractory therapy.