Collateral hypersensitivity between ZY19489 and piperaquine neutralizes PfCRT-mediated drug efflux and Plasmodium falciparum resistance
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.
Authors
- Igor M. R. Moura (ORCID: https://orcid.org/0000-0003-3279-6894)
- Laura M. Hagenah (ORCID: https://orcid.org/0000-0001-8258-6823)
- John Okombo (ORCID: https://orcid.org/0000-0001-8680-2351)
- Charisse Flerida A. Pasaje (ORCID: https://orcid.org/0000-0002-9780-3680)
- Tarrick Qahash (ORCID: https://orcid.org/0000-0003-2891-3090)
- Heekuk Park (ORCID: https://orcid.org/0000-0001-5815-9717)
- Vinícius Bonatto (ORCID: https://orcid.org/0000-0002-3119-0447)
- Lily Orta
- Matthias Quick (ORCID: https://orcid.org/0000-0002-8620-827X)
- Didier Leroy (ORCID: https://orcid.org/0000-0002-5594-3204)
- Filippo Mancia (ORCID: https://orcid.org/0000-0003-3293-2200)
- Tomas Yeo (ORCID: https://orcid.org/0000-0003-2923-6060)
- Vandana Thathy (ORCID: https://orcid.org/0000-0001-7797-8638)
- Jacquin C. Niles (ORCID: https://orcid.org/0000-0002-6250-8796)
- Sachel Mok (ORCID: https://orcid.org/0000-0002-9605-0154)
- David A. Fidock (ORCID: https://orcid.org/0000-0001-6753-8938)
- Kurt E. Ward (ORCID: https://orcid.org/0000-0002-3614-436X)
- Sunil Kumar Narwal (ORCID: https://orcid.org/0000-0001-5476-9753)
- Elizabeth A. Winzeler (ORCID: https://orcid.org/0000-0002-4049-2113)
- Satish K. Dhingra (ORCID: https://orcid.org/0000-0002-3893-1615)
- Jessica L. Bridgford (ORCID: https://orcid.org/0000-0001-8381-1121)
- Jonathan Kim (ORCID: https://orcid.org/0000-0003-2594-3251)
- Isla Anderson
- Tolla Ndiaye (ORCID: https://orcid.org/0009-0008-3698-1249)
- Rafael V. C. Guido
- Iñigo Angulo-Barturen
- Maria Belén Jiménez-Diaz
- Anne-Catrin Uhlemann
- Manuel Llinás
- Eva Gil-Iturbe
Institutions
- Pennsylvania State University (US)
- Institut Pasteur (FR)
- Universidade de São Paulo (BR)
- Columbia University Irving Medical Center (US)
- New York Psychoanalytic Society and Institute (US)
- University of California San Diego (US)
- Euskadiko Parke Teknologikoa (ES)
- Medicines for Malaria Venture (CH)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1038/s41467-026-70914-1
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bill and Melinda Gates Foundation
- Medicines for Malaria Venture
- National Institute of Allergy and Infectious Diseases