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

Autor: Qiu D; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Pei JV; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Rosling JEO; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Thathy V; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, 10032, USA., Li D; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Xue Y; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Tanner JD; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Penington JS; Bioinformatic Division, The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., Aw YTV; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Aw JYH; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Xu G; Department of Molecular Microbiology & Immunology and Johns Hopkins Malaria Institute, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA., Tripathi AK; Department of Molecular Microbiology & Immunology and Johns Hopkins Malaria Institute, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA., Gnadig NF; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, 10032, USA., Yeo T; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, 10032, USA., Fairhurst KJ; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, 10032, USA., Stokes BH; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, 10032, USA., Murithi JM; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, 10032, USA., Kümpornsin K; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK., Hasemer H; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Dennis ASM; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Ridgway MC; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Schmitt EK; Novartis Pharma AG, Novartis Campus, Basel, 4056, Switzerland., Straimer J; Novartis Institute for Tropical Diseases, Emeryville, CA, 94608, USA., Papenfuss AT; Bioinformatic Division, The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia., Lee MCS; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK., Corry B; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Sinnis P; Department of Molecular Microbiology & Immunology and Johns Hopkins Malaria Institute, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA., Fidock DA; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, 10032, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA., van Dooren GG; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Kirk K; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia., Lehane AM; Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia. adele.lehane@anu.edu.au.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Sep 30; Vol. 13 (1), pp. 5746. Date of Electronic Publication: 2022 Sep 30.
DOI: 10.1038/s41467-022-33403-9
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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