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

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Journal:
Cell chemical biology, Volume: 29, Issue: 5
Published:
May 19, 2022
PMID:
34233174
Authors:
James M Murithi JM, Ioanna Deni I, Charisse Flerida A Pasaje CFA, John Okombo J, Jessica L Bridgford JL, Nina F Gnädig NF, Rachel L Edwards RL, Tomas Yeo T, Sachel Mok S, Anna Y Burkhard AY, Olivia Coburn-Flynn O, Eva S Istvan ES, Tomoyo Sakata-Kato T, Maria G Gomez-Lorenzo MG, Annie N Cowell AN, Kathryn J Wicht KJ, Claire Le Manach C, Gavreel F Kalantarov GF, Sumanta Dey S, Maëlle Duffey M, Benoît Laleu B, Amanda K Lukens AK, Sabine Ottilie S, Manu Vanaerschot M, Ilya N Trakht IN, Francisco-Javier Gamo FJ, Dyann F Wirth DF, Daniel E Goldberg DE, Audrey R Odom John AR, Kelly Chibale K, Elizabeth A Winzeler EA, Jacquin C Niles JC, David A Fidock DA
Abstract:

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.