Associated clinical and molecular markers of resistance to antimalarial drugs
Blasco B, Leroy D, Fidock DA. Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic. Nat Med. 2017 23(8):917-928. PMID: 28777791.                  
Antimalarial class Antimalarial name (abbreviation) Major clinical use Affected pathway(s), mechanism(s) Location of target(s) Target molecule(s) Molecular marker of (partial) resistance in field samples Genetic change associated with (partial) resistance in the field Molecular marker(s) of (partial) resistance selected in vitro  Transfection-based confirmation 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 Pleitropic, triggers parasite stress response Uncertain, possibly in cytosol and digestive vacuole Unknown, involves alkylation and oxidation of heme, multiple proteins and lipids Mutations in K13 K13 N458Y, Y493H, R539T, I543T, R561H, C580Y* K13 M476I; pfmdr1 amplification K13 Y493H, R539T, I543T, C580Y major determinants. Modulatory role for pfmdr1 copy number. One single K13 mutation permitted at a time; C580Y fitness neutral in current Cambodian parasites
4-aminoquinolines Chloroquine (CQ) Treatment of non-falciparum malaria Heme detoxification Digestive vacuole b-hematin Mutations in pfcrt and pfmdr1 PfCRT K76T plus 3 or more mutations. PfMDR1 N86Y augments resistance PfCRT K76I/N PfCRT variants major determinant. Secondary role for PfMDR1 N86Y Mutant pfcrt in Africa less fit, overtaken by wild-type allele upon removal of CQ pressure. Fitness-neutral pfcrt allele present in SE Asia
Amodiaquine (AQ) Partner drug for ACT (ASAQ) PfCRT K76T and PfMDR1 N86Y  No published data PfCRT and PfMDR1 mutations Reduced fitness observed with mutant pfcrt and pfmdr1
Piperaquine (PPQ) Partner drug for ACT (DHA-PPQ) Copy number of plasmepsin 2 Amplification of plasmepsins 2 and 3. Associated with pfmdr1 deamplification. Potential contribution from novel PfCRT variants. PfCRT C101F PfCRT C101F No published data
Pyronaridine (PND) Partner drug for ACT (PA) None observed No reliable markers identified so far No published data No published data No published data
8-aminoquinolines Primaquine (PQ) Radical cure and terminal prophylaxis of P. vivax and P. ovale; gametocytocidal drug for P. falciparum Unknown Unknown Unknown None observed No reliable markers identified so far No published data No published data No published data
Antifolates Pyrimethamine (PYR) Used in Sulfadoxine-Pyrimethamine combination (Fansidar™) mostly for intermittent preventive treatment Folate biosynthesis Cytosol DHFR Mutations in dhfr and dhps  DHFR N51I, C59R, S108N*  (predominant in Africa); DHFR N51I, C59R, S108N* and I164L (predominant in Southeast Asia)  DHFR D54N and F223S; pfgch1amplification DHFR N51I, C59R, S108N; pfgch1 amplification Some DHFR mutations alter enzyme kinetics;  pfgch1 amplification is a possible fitness-compensatory mechanism. Fitness cost might be greater for mutant dhfr than for mutant dhps. 
Proguanil (PG) see atovaquone-proguanil See cycloguanil No published data No published data
Cycloguanil (CYC) Metabolically converted from proguanil; see atovaquone-proguanil DHFR A16V and S108T*/N  pfgch1 amplification pfgch1 amplification
Sulfadoxine (SDX) See pyrimethamine  DHPS DHPS S436A/F, A437G*, K540E*, A581G, A613S/T No published data DHPS S436A/F, A437G*, K540E, A581G, A613S
Aryl-amino alcohols Quinine (QN) Treatment of P. falciparum uncomplicated malaria in first trimester of pregnancy, or severe malaria  Unknown Unknown, possibly in cytosol and digestive vacuole Unknown Mostly pfmdr1 amplification Undefined and multifactorial; involves  pfmdr1 amplification or variant forms of pfcrt or pfmdr1 No published data pfmdr1 copy number; variants of pfmdr1 and pfcrt  pfmdr1 overexpression imparts fitness cost
Lumefantrine (LMF) Partner drug for ACT (AL) pfmdr1 amplification; some loss of susceptibility with wild-type PfMDR1 N86 and PfCRT K76 pfmdr1 copy number; variants of pfmdr1 and pfcrt
Mefloquine (MFQ) Partner drug for ACT (ASMQ) and prophylaxis (Lariam™ and generic) As per lumefantrine pfmdr1 amplification pfmdr1 copy number; variants of pfmdr1 and pfcrt
Antibiotics  Clindamycin (CLD) Prophylaxis; treatment in combination with quinine Protein synthesis Apicoplast 23S rRNA  Mutations in apicoplast rRNA apicoplast 23S rRNA A1875C  No published data No published data No published data
Doxycycline (DOX) Prophylaxis for non-immune travelers; treatment in combination with quinine 16S rRNA No reliable markers identified so far
Naphthoquinones Atovaquone (ATQ) Used in combination with proguanil (Malarone™ and generic) Electron transport chain required for pyrimidine biosynthesis Mitochondria Cytochrome bc1 complex Mutation(s) in cytb CYTb Y268S*/C/N  CYTb M133I*, V259L, K272R, P275T, G280D; L283I, V284K  No published data Y268S associated with decreased enzyme activity; cytb mutants failed to produce sporozoites in mosquitoes and therefore are non-transmissible
*Key mutation; 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; rRNA: ribosomal RNA.
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