Modes of action of the antimalarial compound SC83288 in P. falciparum

The emergence of multi-drug resistant Plasmodium falciparum underscores the urgent need for new antimalarial therapies. SC83288, a novel chemical entity, 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 tRNAAsp 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 novel 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.