Currently artemisinin (ART) combination therapies (ACTs) are the only universally effective treatments vs all malaria worldwide. Troublingly however, a harbinger of ART drug resistance (ArtR) has emerged in South East Asia, referred to as the delayed clearance phenotype (DCP). Elucidation of the molecular mechanism of DCP/ArtR is one of the most pressing issues in infectious disease research today. Multiple genetic determinants have been described for DCP, with the most common being mutations in the PfK13 gene, but currently no single unifying molecular mechanism for DCP is known. Our group has been the first to apply targeted metabolomics to the analysis of ART drug pharmacology and ArtR. In essence our malarial parasite culture, fractionation, and extraction methods, combined with liquid chromatography - mass spectrometry (LCMS) techniques, have allowed us to quantify, for the first time, ART drug - FPIX heme covalent adducts formed within live malarial parasites. Our hypothesis is that ART drug - FPIX heme adduct formation correlates with ArtR, and that adduct abundance predicts the severity of ArtR (fold ArtR). We will use these newly perfected methods to test the attractive hypothesis that adduct abundance is correlated with the degree of severity of evolving ArtR. Our work will be comprehensive and span analysis of adducts formed vs multiple natural and synthetic ART drugs and ACT combinations, as well as multiple types of ArtR parasites that harbor all common PfK13 mutations or that do not appear to harbor PfK13 mutations at all.
'Artemisinin activation in artemisinin resistant malarial parasites' Project Narrative Due to widespread drug resistance, currently the artemisinin class of antimalarial drugs are the only remaining universally effective drugs for treating all malaria worldwide. Troublingly, artemisinin resistance (ArtR) may be emerging. This proposal tests an attractive unifying molecular hypothesis for the mechanism of ArtR.
