Apicomplexan parasites contain an essential plastid organelle called the apicoplast. Given its unique features, the apicoplast is a source of novel eukaryotic biology in these parasites and a potential Achilles'heel for drug and vaccine development. The challenge in taking advantage of the apicoplast's unique biology for therapeutic development has been to identify the specific pathways and functions that can be targeted. My overall goal is to elucidate the novel pathways and functions of the apicoplast in two important human pathogens: Plasmodium spp parasites, a leading global infectious disease killer, and Babesia spp parasites, an emerging human infection that threatens the transfusion blood supply. In an important step towards this goal, I recently demonstrated that the sole essential function of the apicoplast in blood-stage P. falciparum is the biosynthesis of isoprenoid precursor, IPP. As such, P. falciparum parasites that have completely lost their apicoplast can be rescued by supplementation with IPP. Significantly, chemical rescue of """"""""apicoplast(-)"""""""" parasites enables new approaches and novel experiments as outlined in this application. I investigate several novel aspects of apicoplast biology: 1) identification of protein factors required for a critical and unique step during protein import into the apicoplast, 2) identificatio of the small molecule isoprenoids derived from IPP that likely have essential cellular functions in P. falciparum, and 3) determination of the function of the apicoplast in Babesia parasites, which share important pathogenic and evolutionary features with P. falciparum. The scope of these aims allows a thorough investigation of the novel features of the Apicoplexan apicoplast that will yield fascinating eukaryotic biology and promising therapeutic targets.
Apicomplexan parasites which include Plasmodium falciparum, cause of the most deadly form of human malaria, and Babesia spp parasites, an emerging threat to the transfusion blood supply, contain a unique plastid organelle that is a potential Achilles'heel for drug development. In this application, I propose to better understand the novel biology of the organelle and its role in the pathogenesis. This work has direct and significant implications for development of novel therapeutics against these important human pathogens.
|Wu, Wesley; Herrera, Zachary; Ebert, Danny et al. (2015) A chemical rescue screen identifies a Plasmodium falciparum apicoplast inhibitor targeting MEP isoprenoid precursor biosynthesis. Antimicrob Agents Chemother 59:356-64|