Abstract

Plasmodium falciparum remained the deadliest malaria parasite, causing over 600,000 deaths annually, with 
antimalarial drug resistance threatening global control efforts. Multiple resistance mechanisms have emerged 
against quinolines, antifolates, and artemisinin-based combinations, compromising therapeutic efficacy across 
endemic regions. This review examined the molecular mechanisms underlying antimalarial drug resistance in 
Plasmodium falciparum and evaluates emerging therapeutic strategies to combat resistant parasites. A 
comprehensive literature search of PubMed, Web of Science, and Cochrane databases identified peer-reviewed 
articles published between 2014 and 2025, prioritizing studies on resistance genetics, biochemical mechanisms, and 
novel drug development. Resistance mechanisms involved genetic mutations in drug target proteins (PfCRT, 
PfMDR1, PfDHFR, PfDHPS, kelch13), altered drug metabolism through efflux transporters, enhanced DNA repair 
pathways, and metabolic adaptations. Chloroquine resistance mediated by PfCRT mutations remains widespread, 
while kelch13 polymorphisms confer artemisinin resistance through enhanced oxidative stress responses and cell 
cycle modulation. Emerging strategies included triple artemisinin-based combinations, synthetic peroxides, 
spiroindolones targeting PfATP4, aminoacyl-tRNA synthetase inhibitors, proteasome inhibitors, and monoclonal 
antibodies. Combination therapies exploiting synergistic mechanisms and targeting multiple parasite stages 
demonstrate promising efficacy against resistant strains. Multifaceted resistance mechanisms necessitate integrated 
approaches combining genomic surveillance, rational drug design, combination therapies, and transmission-blocking 
interventions. Strategic deployment of emerging therapeutics alongside enhanced pharmacovigilance offers renewed 
hope for malaria elimination despite escalating resistance challenges.