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Malaria remains a leading cause of morbidity and mortality in the tropics and subtropics, being responsible for an estimated 500 million clinical cases and 1 million deaths annually. Options to control the spread of malaria are becoming increasingly limited since widely used antimalarials are losing their efficacy, including the 4-aminoquinoline drug chloroquine and the folate antagonists pyrimethamine and sulfadoxine. Moreover, reduced susceptibility has emerged to other antimalarials, including quinine, mefloquine, and possibly artemether.
In both microorganisms and tumours, drug resistance can arise from the presence of P-glycoproteins (P-gp) that are capable of extruding a broad range of structurally and functionally unrelated cytotoxic agents. P-gps belong to the ABC (ATP-binding cassette) transporter superfamily and are encoded by mdr genes. The human malaria parasite Plasmodium falciparum possesses an mdr homologue (pfmdr1) whose gene product, Pgh-1 (also known as PfMDR1), is expressed during intraerythrocytic development of the parasite. Pgh-1 is predominately located at the membrane of the parasite’s digestive vacuole. How polymorphisms within this transporter mediate anti-malarial drug responsiveness has remained obscure.
Using methods focused on live cell imaging and molecular biology, we aim to achieve a better understanding of the mechanisms involved in drug resistance in the intraerythrocytic stages of Plasmodium falciparum.