Drug Resistance Mutations Enhance Growth of Malaria Parasite

Mosquito Some mutations that enable drug resistance in the malaria-causing parasite Plasmodium falciparum may also help it grow.

Plasmodium falciparum is a single-celled parasite that infects the human bloodstream and causes the most severe form of malaria. Some strains of P. falciparum have evolved resistance to antimalarial drugs, including the commonly used drug chloroquine. Often, chloroquine resistance mutations hinder P. falciparum’s ability to infect the bloodstream and grow. However, a previous study discovered that a uniquely mutated version of the P. falciparum gene known as pfcrt provides drug resistance while avoiding the detrimental impact of growth seen with more widely distributed mutated pfcrt variants. In a new study, an allele of the pfcrt gene called Cam734, which has been found in certain regions in Southeast Asia, was shown to increase growth rates in living parasites.

Cam734 helps to maintain an electrochemical gradient that allows the protein encoded by pfcrt to thwart the cellular effects of chloroquine. These new findings broaden understanding of Cam734, the second most common variant of the pfcrt gene in Southeast Asia. The findings identify multiple intracellular processes and multidrug resistance phenotypes impacted by changes in PfCRT and can help inform future malaria treatment efforts.


Evolution of Fitness Cost-Neutral Mutant PfCRT Conferring P. falciparum 4-Aminoquinoline Drug Resistance Is Accompanied by Altered Parasite Metabolism and Digestive Vacuole Physiology. (2016) PLoS Pathog 12(11): e1005976. doi: 10.1371/journal.ppat.1005976
Point mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) earlier thwarted the clinical efficacy of chloroquine, the former gold standard, and consti- tute a major determinant of parasite susceptibility to antimalarial drugs. Recently, we reported that the highly mutated Cambodian PfCRT isoform Cam734 is fitness-neutral in terms of parasite growth, unlike other less fit isoforms such as Dd2 that are outcompeted by wild-type parasites in the absence of CQ pressure. Using pfcrt-specific zinc-finger nucle- ases to genetically dissect the Cam734 allele, we report that its unique constituent mutations directly contribute to CQ resistance and collectively offset fitness costs associated with intermediate mutational steps. We also report that these mutations can contribute to resis- tance or increased sensitivity to multiple first-line partner drugs. Using isogenic parasite lines, we provide evidence of changes in parasite metabolism associated with the Cam734 allele compared to Dd2. We also observe a close correlation between CQ inhibition of hemozoin formation and parasite growth, and provide evidence that Cam734 PfCRT can modulate drug potency depending on its membrane electrochemical gradient. Our data highlight the capacity of PfCRT to evolve new states of antimalarial drug resistance and to offset associated fitness costs through its impact on parasite physiology and hemoglobin catabolism.

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