There is an immediate and dire need to rapidly identify and prioritize antimalarial drug combinations for clinical use. Combination therapy has the best chance of reducing the frequency at which new drug resistance phenomena emerge, and our preliminary data suggest that dozens of previously unrecognized drug combinations with high degrees of synergy can be rapidly identified by our new approach. We will leverage the considerable complementary expertise of five consortium laboratories to identify, prioritize and optimize novel combination drug therapy for drug resistant Plasmodium falciparum malaria. In this effort we will use state of the art high throughput screening capabilities of the National Center for Advanced Translational Science (NCATS), as well as a recently perfected in vitro apparatus that exposes P. falciparum to programmable, dynamically changing drug concentrations. We will also validate potentiation of both 48 hr parasite reduction and 28 day cure using an innovative pharmacodynamic mouse malaria model.
Effective antimalarial therapy is threatened by delayed parasite clearance to the artemisinin class of drugs. This work will identify novel combinations of existing approved drugs which can either augment artemisinin killing while deterring artemisinin partner drug resistance or surpass the parasite killing rates of the artemisinins and the quinolines.
|Hassett, Matthew R; Sternberg, Anna R; Riegel, Bryce E et al. (2017) Heterologous Expression, Purification, and Functional Analysis of Plasmodium falciparum Phosphatidylinositol 3'-Kinase. Biochemistry 56:4335-4345|
|Hassett, Matthew R; Sternberg, Anna R; Roepe, Paul D (2017) Inhibition of Human Class I vs Class III Phosphatidylinositol 3'-Kinases. Biochemistry 56:4326-4334|
|Walker, Leah A; Sullivan Jr, David J (2017) Impact of Extended Duration of Artesunate Treatment on Parasitological Outcome in a Cytocidal Murine Malaria Model. Antimicrob Agents Chemother 61:|
|Caton, Emily; Nenortas, Elizabeth; Bakshi, Rahul P et al. (2016) Hollow-Fiber Methodology for Pharmacokinetic/Pharmacodynamic Studies of Antimalarial Compounds. Curr Protoc Chem Biol 8:29-58|
|Ghaste, Manoj; Mistrik, Robert; Shulaev, Vladimir (2016) Applications of Fourier Transform Ion Cyclotron Resonance (FT-ICR) and Orbitrap Based High Resolution Mass Spectrometry in Metabolomics and Lipidomics. Int J Mol Sci 17:|
|Siriwardana, A; Iyengar, K; Roepe, P D (2016) Endoperoxide Drug Cross-Resistance Patterns for Plasmodium falciparum Exhibiting an Artemisinin Delayed-Clearance Phenotype. Antimicrob Agents Chemother 60:6952-6956|
|Mott, Bryan T; Eastman, Richard T; Guha, Rajarshi et al. (2015) High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations. Sci Rep 5:13891|
|Sherlach, Katy S; Roepe, Paul D (2014) Determination of the cytostatic and cytocidal activities of antimalarial compounds and their combination interactions. Curr Protoc Chem Biol 6:237-48|