Genetic analysis in mice identifies cysteamine as a novel partner for artemisinin in the treatment of malaria

Malaria continues to be a serious threat to global health. The malaria problem is compounded by the absence of an efficacious vaccine and widespread drug resistance in the Plasmodium malarial parasite. The host factors and parasite virulence determinants that regulate early response to infection and subsequent onset of protective immunity are poorly understood. The molecular characterization of this early host:pathogen interface may identify novel targets for prophylactic or therapeutic intervention. Genetic analyses in mouse model of malaria show that inactivation of the enzyme pantetheinase (Char9 locus) causes susceptibility to blood-stage infection. The pantetheinase product cysteamine is an inexpensive and non-toxic aminothiol that is approved for lifelong clinical management of nephropathic cystinosis. In mouse models of infection, cysteamine not only displays anti-malarial activity of its own, but also dramatically potentiates the anti-malarial activity of artemisinin, at doses currently used for the clinical management of cystinosis. Therefore, the inclusion of cysteamine in current artemisinin combination therapies may significantly increase efficacy and may also prove effective against emerging artemisinin-resistant human Plasmodium parasite.