Mechanisms of PfDNMT2 inhibition and PfATP6-mediated resistance to the antimalarial candidate SC83288 in Plasmodium falciparum

Abstract The emergence of multi-drug resistant Plasmodium falciparum underscores the urgent need for new antimalarial therapies. SC83288, a chemically distinct antimalarial compound, is highly effective against P. falciparum both in vivo and in vitro, including strains resistant to artemisinin and partner drugs. Here, we show that SC83288 disrupts blood-stage development by blocking DNA replication and arresting karyokinesis. We identify the parasite’s DNA and tRNA Asp methyltransferase PfDNMT2 as a primary molecular target, linking drug action to impaired epigenetic regulation, altered S-adenosylmethionine fluxes, and compensatory transcriptional responses. Resistance to SC83288 arises through mutations in the parasite’s SERCA-type Ca²⁺ ATPase PfATP6, which enable transport of the compound into the endoplasmic reticulum, away from its nuclear targets. This resistance mechanism carries a substantial fitness cost, limiting its potential for spread. Together, target validation, a unique resistance profile, and high fitness cost strengthen SC83288’s potential as a promising clinical development candidate for malaria treatment.