| Associated clinical and molecular
markers of resistance to antimalarial drugs |
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| 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. |
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| 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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