Identification of genetic markers of quinine partial resistance in Plasmodium falciparum

The genetic basis of Plasmodium falciparum resistance to quinine, a drug used to treat severe malaria, has long been unclear. To investigate this, here we used a human liver-chimaeric mouse model to conduct a P. falciparum genetic cross between quinine-partially resistant and quinine-sensitive parasites. Drug profiling and quantitative trait loci analyses of 120 unique recombinant progeny mapped resistance to segments on chromosomes 7 and 12, indicating a polygenic basis. The chloroquine resistance transporter PfCRT and a structurally similar putative drug/metabolite transporter, DMT1, were identified as primary chromosome 7 candidates based on gene-editing studies. In a proteoliposome assay, both mutant DMT1 and PfCRT transported more quinine than their wild-type isoforms. DMT1 localized to the P. falciparum digestive vacuole, lipid bodies, parasitophorous vacuolar membrane and structures associated with vesicular trafficking. An ATP-dependent zinc metalloprotease (FtsH1) on chromosome 12 also modulated quinine and chloroquine resistance. We suggest that genotypic surveillance of these markers should be performed in clinical settings of quinine use.