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Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials.
- Source :
-
ACS chemical biology [ACS Chem Biol] 2015 Feb 20; Vol. 10 (2), pp. 413-20. Date of Electronic Publication: 2014 Nov 05. - Publication Year :
- 2015
-
Abstract
- Aminopyrazoles are a new class of antimalarial compounds identified in a cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism of action and thus identify their target, we cultured parasites in the presence of a representative member of the aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing of three resistant lines showed that each had acquired independent mutations in a P-type cation-transporter ATPase, PfATP4 (PF3D7_1211900), a protein implicated as the novel Plasmodium spp. target of another, structurally unrelated, class of antimalarials called the spiroindolones and characterized as an important sodium transporter of the cell. Similarly to the spiroindolones, GNF-Pf4492 blocks parasite transmission to mosquitoes and disrupts intracellular sodium homeostasis. Our data demonstrate that PfATP4 plays a critical role in cellular processes, can be inhibited by two distinct antimalarial pharmacophores, and supports the recent observations that PfATP4 is a critical antimalarial target.
- Subjects :
- Adenosine Triphosphatases genetics
Antimalarials chemistry
Indoles chemistry
Indoles pharmacology
Models, Molecular
Molecular Structure
Mutation
Plasmodium falciparum genetics
Protein Conformation
Pyrazoles chemistry
Pyrazoles pharmacology
Sodium metabolism
Adenosine Triphosphatases metabolism
Antimalarials pharmacology
Drug Resistance
Gene Expression Regulation, Enzymologic drug effects
Plasmodium falciparum enzymology
Plasmodium falciparum metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 10
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 25322084
- Full Text :
- https://doi.org/10.1021/cb500616x