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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 |
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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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