A Proteasome Mutation Sensitizes P.falciparum Cam3.II K13C580Y Parasites to DHA and OZ439.

Abstract

Artemisinin-based combination therapies (ACTs), the World Health Organization-recommended first-line therapy for uncomplicated falciparum malaria, has led to significant decreases in malaria-associated morbidity and mortality in the past two decades. Decreased therapeutic efficacy of artemisinins, the cornerstone of ACTs, is threatening the gains made against this disease. As such, novel therapeutics with uncompromised mechanisms of action are needed to combat parasite-mediated antimalarial resistance. We have previously reported the antimalarial activity of Plasmodium falciparum-specific proteasome inhibitors in conjunction with a variety of antimalarials in clinical use or in preclinical investigations and of proteasome mutants generated in response to these inhibitors. Here, we discover that despite harboring K13C580Y, which has conventionally mediated artemisinin resistance in vitro as measured by increased survival in ring-stage survival assays (RSA), the Cam3.II strain parasites of Cambodian origin that have acquired an additional mutation in the proteasome display increased susceptibility to DHA and OZ439. This discovery implicates the proteasome in peroxide susceptibilities and has favorable implications on the use of peroxide and proteasome inhibitor combination therapy for the treatment of artemisinin-resistant malaria.