The Plasmodium falciparum ABC transporter ABCI3 confers parasite strain-dependent pleiotropic antimalarial drug resistance

James M. Murithi, Ioanna Deni, Charisse Flerida A. Pasaje, John Okombo, Jessica L. Bridgford, Nina F. Gnädig, Rachel L. Edwards, Tomas Yeo, Sachel Mok, Anna Y. Burkhard, Olivia Coburn-Flynn, Eva S. Istvan, Tomoyo Sakata-Kato, Maria G. Gomez-Lorenzo, Annie N. Cowell, Kathryn J. Wicht, Claire Le Manach, Gavreel F. Kalantarov, Sumanta Dey, Maëlle DuffeyBenoît Laleu, Amanda K. Lukens, Sabine Ottilie, Manu Vanaerschot, Ilya N. Trakht, Francisco Javier Gamo, Dyann F. Wirth, Daniel E. Goldberg, Audrey R. Odom John, Kelly Chibale, Elizabeth A. Winzeler, Jacquin C. Niles, David A. Fidock

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Widespread Plasmodium falciparum resistance to first-line antimalarials underscores the vital need to develop compounds with novel modes of action and identify new druggable targets. Here, we profile five compounds that potently inhibit P. falciparum asexual blood stages. Resistance selection studies with three carboxamide-containing compounds, confirmed by gene editing and conditional knockdowns, identify point mutations in the parasite transporter ABCI3 as the primary mediator of resistance. Selection studies with imidazopyridine or quinoline-carboxamide compounds also yield changes in ABCI3, this time through gene amplification. Imidazopyridine mode of action is attributed to inhibition of heme detoxification, as evidenced by cellular accumulation and heme fractionation assays. For the copy-number variation-selecting imidazopyridine and quinoline-carboxamide compounds, we find that resistance, manifesting as a biphasic concentration-response curve, can independently be mediated by mutations in the chloroquine resistance transporter PfCRT. These studies reveal the interconnectedness of P. falciparum transporters in overcoming drug pressure in different parasite strains.

Original languageEnglish
Pages (from-to)824-839.e6
JournalCell Chemical Biology
Issue number5
StatePublished - May 19 2022


  • ABCI3
  • CRISPR/Cas9
  • Plasmodium falciparum malaria
  • biphasic dose-response curves
  • cellular accumulation assays
  • conditional knockdowns
  • copy-number variations
  • heme fractionation
  • pfcrt


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