Genomic Plasticity and Molecular Mechanisms of Antimalarial Drug Resistance in Plasmodium falciparum: Implications for Treatment Failure and Genomic Surveillance.

Malaria remains a major global public health challenge, in part because Plasmodium falciparum populations can acquire and disseminate reduced susceptibility to antimalarial drugs under selective pressure. This review synthesizes current evidence on the molecular and genomic mechanisms underlying antimalarial drug resistance and examines their implications for treatment efficacy and malaria control. First, the review examines genomic plasticity, including structural genome variation, copy-number variation, recombination, epigenetic regulation, and transcriptional regulation, as sources of genetic and phenotypic variation relevant to drug susceptibility. Second, it summarizes established molecular determinants of resistance, including kelch13 (K13) mutations associated with delayed parasite clearance following artemisinin treatment, pfcrt mutations associated with chloroquine resistance, pfmdr1 copy-number variation associated with altered susceptibility to mefloquine and related antimalarials, and dhfr and dhps mutations associated with sulfadoxine-pyrimethamine resistance. Third, the review considers the emergence and dissemination of resistance-associated variants across parasite populations, emphasizing the contributions of population genomics and genomic surveillance to monitoring resistance patterns. Finally, recent applications of genomic epidemiology, whole-genome sequencing, and artificial intelligence-assisted analytical approaches are discussed, with emphasis on their potential utility for resistance surveillance and evidence-informed malaria control. Overall, integrating molecular, genomic, epidemiological, and evolutionary information provides a stronger framework for understanding antimalarial resistance and for supporting surveillance, treatment optimization, and malaria-control strategies.