Chloroquine, long the default first-line treatment against
malaria, is now abandoned in large parts of the world because of widespread drug-resistance in Plasmodium falciparum. In spite of its importance as a cost-effective and efficient
drug, a coherent understanding of the cellular mechanisms affected by
chloroquine and how they influence the fitness and survival of the parasite remains elusive. Here, we used a systems biology approach to integrate genome-scale transcriptomics to map out the effects of
chloroquine, identify targeted metabolic pathways, and translate these findings into mechanistic insights. Specifically, we first developed a method that integrates transcriptomic and metabolomic data, which we independently validated against a recently published set of such data for Krebs-cycle mutants of P. falciparum. We then used the method to calculate the effect of
chloroquine treatment on the metabolic flux profiles of P. falciparum during the intraerythrocytic developmental cycle. The model predicted dose-dependent inhibition of DNA replication, in agreement with earlier experimental results for both
drug-sensitive and
drug-resistant P. falciparum strains. Our simulations also corroborated experimental findings that suggest differences in
chloroquine sensitivity between ring- and schizont-stage P. falciparum. Our analysis also suggests that metabolic fluxes that govern reduced
thioredoxin and
phosphoenolpyruvate synthesis are significantly decreased and are pivotal to
chloroquine-based inhibition of P. falciparum DNA replication. The consequences of impaired
phosphoenolpyruvate synthesis and redox metabolism are reduced carbon fixation and increased oxidative stress, respectively, both of which eventually facilitate killing of the parasite. Our analysis suggests that a combination of
chloroquine (or an analogue) and another
drug, which inhibits carbon fixation and/or increases oxidative stress, should increase the clearance of P. falciparum from the host system.