Impacts of Drug Resistance on the Fitness and Metabolism of Plasmodium falciparum

Malaria effects nearly a quarter of a billion people each year. Efforts to control the disease have been hampered by the development of drug resistance in the Plasmodium parasite. This history of drug selections on the parasite have shaped its genome, enhancing drug resistance and compensating for fitness costs associated with the resistance phenotype.

The reshaping of drug resistant parasite genomes will constrain loci particularly important to parasite fitness. Consistent with the hypothesis that the genome of the drug resistant Dd2 parent has been fined tuned to compensate for the effects of drug resistantce we found that parental allele combinations were found at a greater frequency in the progeny of a genetic cross.

Growth dynamics of individual parasite clones in mixed infections were further investigated through the development of a quantitative competition assay that allowed for precise quantitifiation of growth dynamics, specifically the absolute quantification of each parasite within a multiclonal infection. In a mixed infection consisting of drug sensitive and drug resistant parasites the application of drug pressure leads to the competitive release of the drug resistant parasite.

Impact of drug selection on parasite physiology was investigated by coupling global metabolite analysis and QTL mapping. We propose that the endogenous function of pfcrt is the transport of these small peptides from the digestive vacuole of the parasite to cytoplasm. Knowledge of the endogenous fuction of pfcrt is necessary to begin to understand how drug resistant parasites may have adapted to compensate for any fitness costs associated with resistance mutations.

The compiliation of this work strongly supports the existence of, and identifies key molecular components of, the relationship between past drug selection bottlenecks and growth/fitness traits. These compensatory changes could play critical roles in the origin, persistence and spread of drug resistant parasite populations that have been argued to be more virulent and prone to rapid resistance to new drugs. Knowledge of these pathways and mechanisms will also reveal new drug targets, unique to drug resistant parasites, and could facilitate the rational design of drug combinations to thwart the ever-emerging scourge of multi-drug resistant malaria.