Antimalarial drugs and associated markers of resistance in asexual blood stage parasites
Ross LS, Fidock DA. Elucidating Mechanisms of Drug-Resistant Plasmodium falciparum. Cell Host Microbe. 2019 26(1):35-47. PMID: 31295423.
Antimalarial Name (Abbreviation) Major Clinical Use Affected Pathway(s) or Mechanism(s) Genetic Change Associated with Clinical Resistance Fitness Cost of Resistance Determinant
Antimalarial Class: Endoperoxides
Artemisinins (ARTs): artesunate (AS), artemether (ATM), dihydroartemisinin (DHA) First-line treatment as part of ACTs; intravenous artesunate gold standard to treat severe malaria Pleiotropic; triggers parasite stress response. Alkylates and oxidized heme, multiple proteins, and lipids Mutations in k13 One single K13 mutation permitted at a time; nil to low C580Y in vitro fitness cost depending on genetic background
Antimalarial Class: 4-Aminoquinolines
Chloroquine (CQ) Treatment of non-falciparum malaria Heme detoxification in digestive vacuole Mutations in pfcrt and pfmdr1 Mutant pfcrt in Africa less fit, overtaken by wild-type allele upon removal of CQ
Amodiaquine (AQ) Partner drug for ACT (ASAQ) Heme detoxification in digestive vacuole Mutations in pfcrt and pfmdr1 Reduced fitness observed with mutant pfcrt and pfmdr1
Piperaquine (PPQ) Partner drug for ACT (DHA+PPQ) Heme detoxification in digestive vacuole plasmepsin II and III amplification, pfcrt mutations In vitro fitness cost observed with novel pfcrtmutations
Pyronaridine (PND) Partner drug for ACT (PA) Heme detoxification in digestive vacuole None observed No published data
Antimalarial Class: Aryl-Amino Alcohols
Quinine (QN) Treatment of P. falciparum uncomplicated malaria in first trimester of pregnancy, or severe malaria Might include inhibition of hemoglobin import and/or heme detoxification pfcrt (QN), pfmdr1 amplification and sequence (LMF and MFQ) pfmdr1 overexpression imparts fitness cost
Lumefantrine (LMF) Partner drug for ACT (AL) Might include inhibition of hemoglobin import and/or heme detoxification pfcrt (QN), pfmdr1 amplification and sequence (LMF and MFQ) pfmdr1 overexpression imparts fitness cost
Mefloquine (MFQ) Partner drug for ACT (ASMQ) and prophylaxis (Lariam™ and generic) Might include inhibition of hemoglobin import and/or heme detoxification pfcrt (QN), pfmdr1 amplification and sequence (LMF and MFQ) pfmdr1 overexpression imparts fitness cost
Antimalarial Class: Antifolates
Pyrimethamine (PYR) + Sulfadoxine (SDX) Combination (SP) used mostly for intermittent preventive treatment Folate biosynthesis in parasite cytosol Mutations in dhfr and dhps Some DHFR mutations alter enzyme kinetics; pfgch1 amplification is a possible fitness-compensatory mechanism
Proguanil (PG) see atovaquone-proguanil Folate biosynthesis in parasite cytosol Mutations in dhfr and dhps Some DHFR mutations alter enzyme kinetics; pfgch1 amplification is a possible fitness-compensatory mechanism
Antimalarial Class: Naphthoquinones
Atovaquone (ATQ) Used in combination with proguanil (Malarone™ and generic) Mitochondrial electron transport chain required for pyrimidine biosynthesis Mutation(s) in cytb Y268S associated with decreased enzyme activity; cytb mutants failed to produce sporozoites in mosquitoes and therefore are non-transmissible
Antimalarial Class: 8-Aminoquinolines
Primaquine (PQ) Radical cure and terminal prophylaxis of P. vivax and P. ovale; gametocytocidal drug for P. falciparum Unknown None observed No published data
Tafenoquine Radical cure, terminal prophylaxis, and gametocidal activity for P. vivax and P. falciparum Unknown None observed No published data
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