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. Dennis, Melanie C. Ridgway, Esther K. Schmitt, Judith Straimer, Anthony T. Papenfuss, Marcus C. S. Lee, Ben Corry, Photini Sinnis, David A. Fidock, Giel G. Dooren, Kiaran Kirk and Adele M. Lehane ()
Additional contact information
Deyun Qiu: Australian National University
Jinxin V. Pei: Australian National University
James E. O. Rosling: Australian National University
Vandana Thathy: Columbia University Irving Medical Center
Dongdi Li: Australian National University
Yi Xue: Australian National University
John D. Tanner: Australian National University
Jocelyn Sietsma Penington: The Walter & Eliza Hall Institute of Medical Research
Yi Tong Vincent Aw: Australian National University
Jessica Yi Han Aw: Australian National University
Guoyue Xu: Johns Hopkins School of Public Health
Abhai K. Tripathi: Johns Hopkins School of Public Health
Nina F. Gnadig: Columbia University Irving Medical Center
Tomas Yeo: Columbia University Irving Medical Center
Kate J. Fairhurst: Columbia University Irving Medical Center
Barbara H. Stokes: Columbia University Irving Medical Center
James M. Murithi: Columbia University Irving Medical Center
Krittikorn Kümpornsin: Wellcome Genome Campus
Heath Hasemer: Australian National University
Adelaide S. M. Dennis: Australian National University
Melanie C. Ridgway: Australian National University
Esther K. Schmitt: Novartis Pharma AG, Novartis Campus
Judith Straimer: Novartis Institute for Tropical Diseases
Anthony T. Papenfuss: The Walter & Eliza Hall Institute of Medical Research
Marcus C. S. Lee: Wellcome Genome Campus
Ben Corry: Australian National University
Photini Sinnis: Johns Hopkins School of Public Health
David A. Fidock: Columbia University Irving Medical Center
Giel G. Dooren: Australian National University
Kiaran Kirk: Australian National University
Adele M. Lehane: Australian National University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33403-9

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