Molecular and physiologic basis of quinoline drug resistance in Plasmodium falciparum malaria

30 years before the discovery of the pfcrt gene, altered cellular drug accumulation in drug-resistant malarial parasites had been well documented. Heme released from catabolized hemoglobin was thought to be a key target for quinoline drugs, and additional modifications to quinoline drug structure in order to improve activity against chloroquine-resistant malaria were performed in a few laboratories. However, parasite cell culture methods were still in their infancy, assays for drug susceptibility were not well standardized, and the power of malarial genetics was decades away. The last 10 years have witnessed explosive progress in elucidation of the biochemistry of chloroquine resistance. This review briefly summarizes that progress, and discusses where additional work is needed.