A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin

Deyun Qiu, Jinxin V. Pei, James E. O. Rosling, Vandana Thathy, Dongdi Li, Yi Xue, John D. Tanner, Jocelyn Sietsma Penington, Yi Tong Vincent Aw, Jessica Yi Han Aw, Guoyue Xu, Abhai K. Tripathi, Nina F. Gnadig, Tomas Yeo, Kate J. Fairhurst, Barbara H. Stokes, James M. Murithi, Krittikorn Kümpornsin, Heath Hasemer, Adelaide S. M. DennisMelanie C. Ridgway, Esther K. Schmitt, Judith Straimer, Anthony T. Papenfuss, Marcus C. S. Lee, Ben Corry, Photini Sinnis, David A. Fidock, Giel G. van Dooren, Kiaran Kirk, Adele M. Lehane (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)
46 Downloads (Pure)

Abstract

Diverse compounds target the Plasmodium falciparum Na+ pump PfATP4, with cipargamin and (+)-SJ733 the most clinically-advanced. In a recent clinical trial for cipargamin, recrudescent parasites emerged, with most having a G358S mutation in PfATP4. Here, we show that PfATP4G358S parasites can withstand micromolar concentrations of cipargamin and (+)-SJ733, while remaining susceptible to antimalarials that do not target PfATP4. The G358S mutation in PfATP4, and the equivalent mutation in Toxoplasma gondii ATP4, decrease the sensitivity of ATP4 to inhibition by cipargamin and (+)-SJ733, thereby protecting parasites from disruption of Na+ regulation. The G358S mutation reduces the affinity of PfATP4 for Na+ and is associated with an increase in the parasite's resting cytosolic [Na+]. However, no defect in parasite growth or transmissibility is observed. Our findings suggest that PfATP4 inhibitors in clinical development should be tested against PfATP4G358S parasites, and that their combination with unrelated antimalarials may mitigate against resistance development.

Original languageEnglish
Article number5746
Number of pages18
JournalNature Communications
Volume13
DOIs
Publication statusPublished - 30 Sept 2022

Keywords

  • Malaria
  • Parasite biology

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General
  • General Physics and Astronomy

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