A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin
Date
2022
Authors
Qiu, Deyun
Pei, Victor
Rosling, James
Thathy, Vandana
Li, Dongdi
Xue, Yi
Tanner, John
Sietsma Penington, Jocelyn
Aw, Yi Tong Vincent
Aw, Jessica
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Volume Title
Publisher
Macmillan Publishers Ltd
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.
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Source
Nature Communications
Type
Journal article
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Access Statement
Open Access
License Rights
Creative Commons Attribution 4.0 International License
DOI
10.1038/s41467-022-33403-9