Epigenetic Mechanisms of Drug Tolerance in Plasmodium falciparum Isolates from Nigerian Paediatric Malaria Patients: Implications for Next-Generation Antimalarial Drug Design

Background: Emerging tolerance to artemisinin-based combination therapies in African Plasmodium falciparum strains represents a critical threat to malaria control. While genetic mutations in the PfKelch13 gene have been implicated, epigenetic regulation of drug tolerance through histone modification and chromatin remodelling in African isolates is poorly characterised. This study investigates epigenetic mechanisms underlying drug tolerance in P. falciparum isolates from Nigerian paediatric malaria patients. Methods: Clinical P. falciparum isolates were collected from 80 paediatric malaria patients at teaching hospitals in Ibadan (South West) and Kano (North West). Parasite survival rates after in vitro artemisinin and lumefantrine treatment were quantified. Whole-genome ChIP-seq was used to map H3K9ac and H3K4me3 chromatin marks associated with drug resistance gene expression. Differential epigenetic profiling between tolerant and sensitive isolates was performed using DESeq2. Candidate epigenetic drug targets were evaluated in silico using homology modelling. Results: Drug-tolerant isolates exhibited significant enrichment of H3K9ac marks at stress response and ring-stage survival gene loci. Three histone acetyltransferase genes showed differential expression in tolerant strains. In silico screening identified two chemical scaffolds with selective inhibitory activity against P. falciparum GNAT-family histone acetyltransferases. Conclusion: Epigenetic regulation contributes to artemisinin tolerance in Nigerian P. falciparum isolates through histone acetylation remodelling. P. falciparum histone acetyltransferases represent viable next-generation antimalarial drug targets. Keywords: Plasmodium falciparum, epigenetics, artemisinin tolerance, histone acetylation, antimalarial design