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

Qiu, D; Pei, JV; Rosling, JEO; Thathy, V; Li, D; Xue, Y; Tanner, JD; Penington, JS; Aw, YTV; Aw, JYH; Xu, G; Tripathi, AK; Gnadig, NF; Yeo, T; Fairhurst, KJ; Stokes, BH; Murithi, JM; Kumpornsin, K; Hasemer, H; Dennis, ASM; Ridgway, MC; Schmitt, EK; Straimer, J; Papenfuss, AT; Lee, MCS; Corry, B; Sinnis, P; Fidock, DA; van Dooren, GG; Kirk, K; Lehane, AM

Author(s): Qiu, D; Pei, JV; Rosling, JEO; Thathy, V; Li, D; Xue, Y; Tanner, JD; Penington, JS; Aw, YTV; Aw, JYH; Xu, G; Tripathi, AK; Gnadig, NF; Yeo, T; Fairhurst, KJ; Stokes, BH; Murithi, JM; Kumpornsin, K; Hasemer, H; Dennis, ASM; Ridgway, MC; Schmitt, EK; Straimer, J; Papenfuss, AT; Lee, MCS; Corry, B; Sinnis, P; Fidock, DA; van Dooren, GG; Kirk, K; Lehane, AM;
Details: Publication Year 2022-09-30,Volume 13,Issue #1,Page 5746
Journal Title: Nature Communications
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 PfATP4(G358S) 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 PfATP4(G358S) parasites, and that their combination with unrelated antimalarials may mitigate against resistance development.
Publisher: NPG
Keywords: Antimalarials/pharmacology/therapeutic use; Erythrocytes/parasitology; Humans; Indoles; Ions; Malaria, Falciparum/drug therapy/parasitology; Mutation; Plasmodium falciparum; Sodium; Spiro Compounds
Research Division(s): Bioinformatics
PubMed ID: 36180431
Publisher's Version: https://doi.org/10.1038/s41467-022-33403-9
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-022-33403-9
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41467-022-33403-9.pdf - (2.06MB, application/pdf)

Creation Date: 2022-10-14 09:03:12

Last Modified: 2022-10-14 09:09:18