title: Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials.
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.
authors.affiliation: Division of Pharmacology and Drug Discovery, Department of Pediatrics, ‡Division of Infectious Diseases, Department of Medicine, University of California San Diego School of Medicine , La Jolla, California 92093, United States.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Flannery
authors.forename: Case W
authors.initials: CW
authors.lastname: McNamara
authors.forename: Sang Wan
authors.initials: SW
authors.lastname: Kim
authors.forename: Tomoyo Sakata
authors.initials: TS
authors.lastname: Kato
authors.forename: Fengwu
authors.initials: F
authors.lastname: Li
authors.forename: Christine H
authors.initials: CH
authors.lastname: Teng
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gagaring
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Manary
authors.forename: Rachel
authors.initials: R
authors.lastname: Barboa
authors.forename: Stephan
authors.initials: S
authors.lastname: Meister
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Vinetz
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D004351:Drug Resistance; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism
chemical_list: D000962:Antimalarials; D007211:Indoles; D011720:Pyrazoles; D012964:Sodium; D000251:Adenosine Triphosphatases