David Fidock | Molecular insights into antimalarial drug resistance

Malaria exerts a devastating impact on communities in the Global South, with upwards of 600,000 deaths yearly, primarily young African children. Using genetic approaches, we have explored the molecular basis of Plasmodium falciparum antimalarial drug resistance, which poses a constant threat to malaria treatment and control efforts. Using a genetic cross, we earlier identified that mutations in PfCRT conferred parasite resistance to chloroquine, the former first-line antimalarial drug. Structural and functional studies reveal that these mutations enable this transporter of globin-derived peptides to efflux chloroquine away from its heme target in parasitized erythrocytes. We also identified novel PfCRT variants that mediate resistance to piperaquine, a first-line combination partner drug that recently failed across Southeast Asia. We and others have also shown that mutations in Kelch13 are causal for parasite resistance to artemisinin, the core component of all current combination therapies, and have identified their emergence in east Africa. Kelch13 mutations affect multiple intracellular processes including hemoglobin endocytosis and degradation, mitochondrial physiology, and artemisinin-induced cellular quiescence. In anticipation that artemisinin partial resistance will lead to this drug becoming ineffective at treating severe malaria, we also have also leveraged a genetic cross to explore parasite susceptibility to quinine, an alternative treatment for severe disease. This work has identified a novel drug-metabolite transporter, DMT1, as a novel determinant of quinine resistance. Our ongoing efforts to identify new therapeutic approaches to treating artemisinin-resistant malaria include developing parasite-specific proteasome inhibitors, which synergize with artemisinin and restore its activity including against resistant parasites. Insights gained into molecular resistance mechanisms and genetic markers are being incorporated into global efforts to mitigate the emergence and spread of multidrug-resistant malaria.