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. van Dooren; Kiaran Kirk; Adele M. Lehane

doi:10.1038/s41467-022-33403-9

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)

Biological Chemistry and Drug Discovery

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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 language	English
Article number	5746
Number of pages	18
Journal	Nature Communications
Volume	13
DOIs	https://doi.org/10.1038/s41467-022-33403-9
Publication status	Published - 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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10.1038/s41467-022-33403-9Licence: CC BY

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Cite this

Qiu, D., Pei, J. V., Rosling, J. E. O., Thathy, V., Li, D., Xue, Y., Tanner, J. D., Penington, J. S., Aw, Y. T. V., Aw, J. Y. H., Xu, G., Tripathi, A. K., Gnadig, N. F., Yeo, T., Fairhurst, K. J., Stokes, B. H., Murithi, J. M., Kümpornsin, K., Hasemer, H., ... Lehane, A. M. (2022). A G358S mutation in the Plasmodium falciparum Na⁺ pump PfATP4 confers clinically-relevant resistance to cipargamin. Nature Communications, 13, Article 5746. https://doi.org/10.1038/s41467-022-33403-9

@article{15432e7c31434b78aecbaeeb6f0dc78e,

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

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.",

keywords = "Malaria, Parasite biology",

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

note = "Funding Information: This work was supported by: an Australian National Health and Medical Research Council Project Grant (GNT1159648) to A.M.L. and K.K.; a contract from Novartis to D.A.F., P.S. and A.K.T.; a Wellcome grant [Grant number 206194/Z/17/Z] to M.C.S.L.; and a National Institutes of Health grant (R01 AI132359) to P.S. Copyright: {\textcopyright} 2022. The Author(s).",

year = "2022",

month = sep,

day = "30",

doi = "10.1038/s41467-022-33403-9",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

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, Kümpornsin, 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 2022, 'A G358S mutation in the Plasmodium falciparum Na⁺ pump PfATP4 confers clinically-relevant resistance to cipargamin', Nature Communications, vol. 13, 5746. https://doi.org/10.1038/s41467-022-33403-9

TY - JOUR

T1 - A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin

AU - Qiu, Deyun

AU - Pei, Jinxin V.

AU - Rosling, James E. O.

AU - Thathy, Vandana

AU - Li, Dongdi

AU - Xue, Yi

AU - Tanner, John D.

AU - Penington, Jocelyn Sietsma

AU - Aw, Yi Tong Vincent

AU - Aw, Jessica Yi Han

AU - Xu, Guoyue

AU - Tripathi, Abhai K.

AU - Gnadig, Nina F.

AU - Yeo, Tomas

AU - Fairhurst, Kate J.

AU - Stokes, Barbara H.

AU - Murithi, James M.

AU - Kümpornsin, Krittikorn

AU - Hasemer, Heath

AU - Dennis, Adelaide S. M.

AU - Ridgway, Melanie C.

AU - Schmitt, Esther K.

AU - Straimer, Judith

AU - Papenfuss, Anthony T.

AU - Lee, Marcus C. S.

AU - Corry, Ben

AU - Sinnis, Photini

AU - Fidock, David A.

AU - van Dooren, Giel G.

AU - Kirk, Kiaran

AU - Lehane, Adele M.

N1 - Funding Information: This work was supported by: an Australian National Health and Medical Research Council Project Grant (GNT1159648) to A.M.L. and K.K.; a contract from Novartis to D.A.F., P.S. and A.K.T.; a Wellcome grant [Grant number 206194/Z/17/Z] to M.C.S.L.; and a National Institutes of Health grant (R01 AI132359) to P.S. Copyright: © 2022. The Author(s).

PY - 2022/9/30

Y1 - 2022/9/30

N2 - 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.

AB - 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.

KW - Malaria

KW - Parasite biology

UR - http://www.scopus.com/inward/record.url?scp=85139536114&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-33403-9

DO - 10.1038/s41467-022-33403-9

M3 - Article

C2 - 36180431

AN - SCOPUS:85139536114

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

M1 - 5746

ER -