MMV Malaria Box Activity Screening in Dormant Plasmodium falciparum Phenotypes

The causative agent of malignant tertian malaria, Plasmodium falciparum undergoes an arrested growth phenotype of its erythrocytic stage when under drug-stress. Recent artemisinin treatment failures seem to be indicative of such induction followed by recrudescence rather than actual therapeutic failure. Likewise, P. vivax hypnozoites are the prototypic dormants and the latent infections for which they are responsible prove most difficult to treat. Dihydroartemisinin, an artemisinin-derivative, can be used to exploit this mechanism by inducing a dormant state in ring-stage P. falciparum parasites and in turn, their recovery may be used as a screening period for compounds that inhibit or foster growth. Specifically, parasites stably transfected with luciferase were used to quantitatively observe growth (or lack thereof) response of parasites to the phytohormone gibberellic acid and the herbicide, fluridone. Using their behavior as comparative controls, the Medicines for Malaria Venture (MMV) Malaria Box was screened for similar activity. The most active compound, 1,2,3,4-tetrahydroacridin-9-ol a quinoline-derivate caused cells to wake even earlier than expected. Since quinine and other such drugs have historically been most effective in treating malaria, it seems appropriate that such a finding was made. Following this the MMV Box was screened again against uninduced 3D7 parasites to determine if any were capable of causing a dormant response under the hypothesis that such a reaction is a defensive adaptation of P. falciparum. Four compounds were found to be active of which two appear to be inducing dormancy in the second cycle rather than the first akin to DHA. These quiescent periods also appear to be shorter indicating that the latter is more efficient. It is possible that given the length of interaction with artemisinin, P. falciparum is more adept to respond to its derivatives likewise the mechanism of action may be different enough to change the nature of the response