Antimalarial Drug Resistance Mechanisms and Emerging Therapeutic Strategies in Plasmodium falciparum Infection
Nalongo Bina K.
Faculty of Medicine Kampala International University Uganda
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.
Keywords: Plasmodium falciparum, Antimalarial resistance, kelch13 mutations, Artemisinin resistance, Emerging therapeutics
CITE AS: Nalongo Bina K. (2026). Antimalarial Drug Resistance Mechanisms and Emerging Therapeutic Strategies in Plasmodium falciparum Infection. IDOSR JOURNAL OF BIOCHEMISTRY, BIOTECHNOLOGY AND ALLIED FIELDS 11(1):95-101. https://doi.org/10.59298/IDOSR/JBBAF/2026/10295101