Apicomplexan parasites include important human pathogens such as Plasmodium spp., Toxoplasma gondii, and Cryptosporidium parvum. Due to a lack of vaccines as well as continuously developing resistance and severe side-effects to currently available treatments, new drugs are needed to treat these infections. While high-throughput small molecule screening has identified numerous anti-malarial lead compounds, it is not known how almost all of these compounds kill Plasmodium. <p/> Understanding these mechanisms is important for two key reasons. First, developing a compound into a drug that can be prescribed to patients requires a thorough understanding of the compound's mechanism of action. Second, drugs work by inhibiting cellular compounds and pathways and discovering what these are reveals new drug targets. Because many Apicomplexan-specific processes are essential for growth of these parasites, it is likely that some of lead anti-malarial lead compounds will also affect growth of other Apicomplexan parasites. In this application, we will take advantage of the genetic and experimental tractability of Toxoplasma gondii to identify compounds from the Malaria Box collection that block growth of both Toxoplasma and Plasmodium. We will then use chemical mutagenesis to isolate drug resistant Toxoplasma parasites and identify the mutations that confer drug resistance in Toxoplasma. The drug resistance alleles will then be examined in Plasmodium falciparum to determine which drug resistance genes are conserved and thus represent pan-Apicomplexan drug targets.
PUBLIC HEALTH RELEVANCE: There is an urgent to discover drug targets in Apicomplexan parasites because these organisms include some of the most important human pathogens. This project's aim is accomplish this goal by using genetic analyses to determine how small molecule compounds kill these parasites.