Resistance mechanisms for clinically important antimalarial drugs
Volkman SK, Herman J, Lukens AK, Hartl DL. Genome-Wide Association Studies of Drug-Resistance Determinants. Trends Parasitol. 2017 33(3):214-230. PMID: 28179098.
Antimalarial drug Loci implicated in resistance (type of mutation) Evidence Opportunities and commentary
Chloroquine pfcrt (SNPs), pfmdr1 (SNPs), pfmrp (SNPs) • Candidate gene approaches in CQR vs. CQS clinical isolates  MQ, LUM, ADQ, and PPQ are all used as partner drugs in ACTs; it is critical to continue to understand the resistance mechanisms for these partner drugs and monitor genetic markers in population studies. The genetic background on which pfcrt and pfmdr1 alleles Fitness effects have been observed with pfcrt and pfmdr1 resistance mutations with population-level return to CQ-sensitivity. These observations suggest that combination therapy strategies utilizing an evolutionary biology fitness-loop could be exploited to promote a drug-sensitive population and suppress the emergence of resistance exist influences their effect in drug-response phenotypes.
• Linkage analysis
• Genetic validation using transgenic over-expression parasites and allelic replacements by Zn-finger nucleases
• Mutations in pfmrp (PfMRP:Y191H and PfMRP:A437S implicated in QN and CQ resistance 
Mefloquine/halofantrine/ lumefantrine pfmdr1, PF10_0355 (SNPs and CNV) • Candidate gene approaches, linkage analysis, GWAS of clinical isolates
• Genetic validation using allelic replacements and Zn-finger nuclease-edited strains (pfmdr1) and transgenic parasites (episomal overexpression, allelic replacement, and knockout approaches)
Amodiaquine pfmdr1 (SNPs and CNV) • PfMDR1 N86Y increases parasite resistance to ADQ
Piperaquine pfmdr1 (SNPs and CNV) • GWAS and in vitro resistance selection 
Quinine pfnhe1 (MS polymorphism), pfmdr1 (SNPs and CNV), pfmrp (SNPs); multiple copies of plasmepsim-2 • QTL mapping identified pfnhe1 locus with MS repeat polymorphisms (ms4760) implicated in modulating QN response  Additional studies have explored ms4760 repeat polymorphisms in field isolates and question its reliability as a broadly applicable marker of QN resistance; its utility might be geographically restricted . Together, these studies demonstrate that response to QN is a complex trait and warrants further study in order to understand its genetic basis.
• pfnhe1 knockdown studies validate role for the locus in modulating QN sensitivities in some genetic backgrounds [118]
• Candidate gene approaches of clinical isolates and GWAS implicate pfmdr1 
• pfmdr1 allelic replacements validated role of SNPs in QN resistance 
• Mutations in pfmrp (PfMRP:Y191H and PfMRP:A437S implicated in QN and CQ resistance.
Multiple copies of plasmepsin-2 are associated with resistance to piperaquine Clinical trial. 30% of PPQ
Primaquine Unknown Instances of clinical resistance have been reported, but the mechanism or marker of this resistance remains unknown. Despite its G6PD liability, primaquine is the only antimalarial in clinical use that provides radical cure for Plasmodium vivax and Plasmodium ovale dormant forms as well as gametocytocidal activity in P. falciparum. Renewed efforts to understand potential resistance mechanisms of this drug, particularly in dormant parasite forms, are critical.
Pyrimethamine pfdhfr (SNPs) • Candidate gene approaches Despite widespread resistance, SP therapy remains useful as an intermittent preventative therapy (IPT) during pregnancy. Additional efforts are needed to identify new antimalarial agents with safety profiles that allow for treatment of pregnant women and young children.
• Validation by in vitro assays
Sulfadoxine pfdhps (SNPs) • Candidate gene approaches 
• Validated by in vitro enzyme assays and allelic replacements 
Artemesinin and derivatives pfmdr1 (SNPs and CNV), kelch13 (SNPs), • in vitro resistance selections and linkage-based GWAS Identified kelch13 as a major locus for ART resistance. Determined that different mutations confer varying degrees of resistance. Evidence provided for possible role of other partners or pathways.
• Genetic validation using Zn-finger nucleases (pfmdr1), (kelch13) and CRISPR-Cas9 editing (kelch13)
• Molecular characterization of resistance
• Indications for other pathways distinct from kelch13
Atovaquone pfcytb (SNPs) • Candidate gene approaches  Synergistic combination with proguanil (Malarone ®) continues to be a widely used prophylactic therapy despite rapid emergence of ATV resistance and recent reports of Malarone failures. ATV-resistance mutations might have fitness costs, including an impact on transmission, which bears further investigation 
Abbreviations: SNPs, single-nucleotide polymorphisms; CQR, chloroquine resistant; CQS, chloroquine sensitive; QN, quinine; CQ, chloroquine; MQ, mefloquine; LUM, lumefantrine; ADQ, amodiaquine; PPQ, piperaquine; ACTs, artemesinin combination therapies; CNV, copy number variation; GWAS, genome-wide association study; MS, microsatellite; QTL, quantitative trait locus; SP, sulfadoxine-pyrimethanie; ATV, atovaquone.
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