Mutations in the P-Type Cation-Transporter ATPase 4, PfATP4, Mediate Resistance to Both Aminopyrazole and Spiroindolone Antimalarials

16 Oct 2014

Erika L. Flannery, Case W. McNamara, Sang Wan Kim, Tomoyo Sakata Kato, Fengwu Li, Christine H. Teng, Kerstin Gagaring, Micah J. Manary, Rachel Barboa, Stephan Meister, Kelli Kuhen, Joseph M. Vinetz, Arnab K. Chatterjee and Elizabeth A. Winzeler

ACS Chemical Biology
DOI: 10.1021/cb500616x

An article on work supported by MMV

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.

View the full article on the ACS Publications website.