Malaria Drug Resistance, Pathogenesis, and Drug Discovery
Malaria is estimated to cause over 210 million clinical episodes and 420,000 deaths each year, mostly in Africa in children under five years of age. The majority of deaths are caused by the intracellular Apicomplexan parasite Plasmodium falciparum, which begins its infection of the human host in hepatocytes and proceeds to the disease-causing and potentially fatal intra-erythrocytic asexual blood stages, before developing into gametocyte sexual stages that are transmissible to Anopheles mosquito vectors. The global adoption of artemisinin-based combination therapies (ACTs) a decade ago heralded a new era in the effective treatment of drug-resistant Plasmodium falciparum malaria, helping to halve numbers of malaria deaths that earlier attained one million individuals yearly. Several Southeast Asian countries, however, have now reported the emergence of parasites with decreased susceptibility to artemisinin derivatives, followed more recently in Cambodia by resistance to the ACT partner drug piperaquine and increasing rates of treatment failures.
Research in the division on malaria focuses on mechanisms of P. falciparum multidrug resistance and research into new antimalarials and elucidation of their modes of action. Work in the Fidock Lab applies gene-editing tools to decipher mechanisms of resistance to artemisinin and heme-binding antimalarials including chloroquine and piperaquine. Notable results have included: The initial discovery of pfcrt as the primary determinant of chloroquine resistance (Fidock et al. 2000 Molec. Cell); The development of gene editing for P. falciparum and its application to studying drug resistance determinants (Straimer et al. 2012 Nature Methods); Genetic proof that mutations in K13 mediate artemisinin resistance in vitro (Straimer et al. 2015 Science); Elucidation of genetic drivers of piperaquine resistance in Cambodia (Ross et al. 2018 Nature Commun., accepted).
Ongoing projects in the Fidock Lab include:
- Implementation of P. falciparum genetic crosses, using the humanized HuHep/RBC FRG-NOD mouse model, to genetically map determinants of multidrug resistance in Asia and South American parasites
- Elucidation of targets and mechanisms of resistance to advanced preclinical or clinical antimalarials
- Discovery of novel drug targets, within the Malaria Drug Accelerator Consortium
- Defining the modes of action of P. falciparum blood and liver-active hits identified in collaboration with the National Center for Advancing Translational Sciences and the Walter Reed Army Institute of Research
- Studies into lipid metabolism throughout the parasite life cycle, including as sensors of host metabolic stress and parasite cell fate
These studies are funded through grants with NIAID, the Department of Defense, the Bill & Melinda Gates Foundation and the Medicines for Malaria Venture.
Marcus Pereira, an Assistant Professor in our Division, previously conducted his fellowship research in the lab, and our current fellow Jen Small-Saunders is a current member. Dr. Fidock, jointly appointed in the Department of Microbiology and Immunology, actively collaborates in the Division with Dr. Uhlemann, whose Microbiome and Pathogen Genomics Core provides whole-genome sequencing for our P. falciparum studies.