Authors
Mariko Kanai, Sachel Mok, Tomas Yeo, Melanie J Shears, Jin H Jeon, Sunil K Narwal, Leila S Ross, Kharizta Wiradiputri, Meseret T Haile, Abhai K Tripathi, Godfree Mlambo, Jonathan Kim, Eva Gil-Iturbe, Heekuk Park, Tolla Ndiaye, John Okombo, Kurt E Ward, Felix D Rozenberg, Kate J Fairhurst, Sydney M Gavula, Talia S Bloxham, Jessica L Bridgford, Tanaya Sheth, Manuel Llinás, Marcus C S Lee, Jennifer L Small-Saunders, Filippo Mancia, Matthias Quick, Anne-Catrin Uhlemann, Photini Sinnis, David Armand Fidock
Published in
Nature microbiology. Jul 06, 2026. Epub Jul 06, 2026.
Abstract
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.
PMID:
42410209
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.
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