Table 1.
Antimalarial drugs and associated markers of resistance in Plasmodium falciparum asexual blood stage parasites.
| Antimalarial class | Antimalarial name (abbreviation) |
Major clinical use | Affected pathway(s), mechanism(s) |
Genetic change associated with clinical resistance |
Fitness cost of resistance determinant |
|---|---|---|---|---|---|
| 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 |
| 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 pressure |
| Amodiaquine (AQ) | Partner drug for ACT (ASAQ) | Reduced fitness observed with mutant pfcrt and pfmdr1 | |||
| Piperaquine (PPQ) | Partner drug for ACT (DHA-PPQ) | plasmepsin II and III amplification, pfcrt mutations | In vitro fitness cost observed with novel pfcrt mutations | ||
| Pyronaridine (PND) | Partner drug for ACT (PA) | None observed | No published data | ||
| 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) | ||||
| Mefloquine (MFQ) | Partner drug for ACT (ASMQ) and prophylaxis (Lariam™ and generic) | ||||
| 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 | ||||
| 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 |
| 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 |
ACTs: artemisinin-based combination therapies; ASAQ: artesunate+amodiaquine; DHA-PPQ: dihydroartemisinin+piperaquine; PA: pyronaridine+artesunate; SP: sulfadoxine+pyrimethamine; AL: artemether+lumefantrine; ASMQ: artesunate+mefloquine; K13: Kelch-like gene; cytb cytochrome b; dhfr: dihydrofolate reductase; dhps: dihydropteroate synthase; gch1: GTP cyclohydrolase I; pfcrt: P. falciparum chloroquine resistance transporter; pfmdr1: P. falciparum multidrug resistance gene-1. Adapted in abbreviated form from Blasco et al., 2017.