The Drug Resistance group validates and characterizes the function of candidate drug resistance genes identified through pharmacogenomic and population genetic strategies. Work includes investigation of when a compound is most effective in the parasite lifecycle (including asexual, sexual and mosquito stages), how quickly resistance arises in vitro and how the compound is killing the parasite. We use CRISPR/CAS9 strategies to generate inducible knock down parasite lines as well as tagged lines to allow us to better characterize the function of the protein of interest. Using this approach, we have been able to show that acetyl-coA synthetase inhibitors affect histone acetylation while inhibition of acyl-coA synthetase 10 leads to a reduction in triacylglycerols. We also identified the prolyl-tRNA synthetase as the direct target and the apicomplexan amino acid transporter (ApiAT2) as a resistance mechanism of halofuginone treatment.
In addition to drug targets identified through the MalDA pipeline, we also investigate how drug resistance evolves to current antimalarials used in the field. We have identified Pfcoronin as a new player in resistance to the artemisinin derivates, the frontline antimalarial in combination therapies. We also investigated to role of plasmepsins in the resistance to piperaquine, a partner drug of artemisinin. We are in the process of further characterizing how those targets protect the parasites from drug treatment using molecular and cell biological techniques.
Collaborators: Niles lab, Catteruccia lab, Susan Wyllie, David Fidock, Elizabeth Winzeler, Marcus Lee, Jeff Dvorin, Sabrina Absalon, Laura Kirkman, Beatriz Barengana, Ralph Mazitschek