Abstract
Artemisinin is the most rapidly effective drug for Plasmodium falciparum malaria treatment currently in clinical use. Emerging artemisinin-resistant parasites pose a great global health risk. At present, the level of artemisinin resistance is still relatively low with evidence pointing towards a trade-off between artemisinin resistance and fitness loss. Here we show that artemisinin-resistant P. falciparum isolates from Cambodia manifested fitness loss, showing fewer progenies during the intra-erythrocytic developmental cycle. The loss in fitness was exacerbated under the condition of low exogenous amino acid supply. The resistant parasites failed to undergo maturation, whereas their drug-sensitive counterparts were able to complete the erythrocytic cycle under conditions of amino acid deprivation. The artemisinin-resistant phenotype was not stable, and loss of the phenotype was associated with changes in the expression of a putative target, Exp1, a membrane glutathione transferase. Analysis of SNPs in haemoglobin processing genes revealed associations with parasite clearance times, suggesting changes in haemoglobin catabolism may contribute to artemisinin resistance. These findings on fitness and protein homeostasis could provide clues on how to contain emerging artemisinin-resistant parasites.
Highlights
Combination therapies (ACTs) can still cure P. falciparum malaria patients, the threat from emerging artemisinin resistance cannot be ignored, since resistance to chloroquine and antifolates both spread from this region to Africa, setting back malaria control and elimination programmes for decades[5,6]
Despite unequivocal observations of delayed parasite clearance time in malaria patients, emerging artemisinin resistance presents a unique challenge since reduced drug susceptibility is largely confined to the ring stage with the more mature stages being relatively unaffected[7]
Fitness loss is a common trade-off during the evolutionary selection of antimicrobial drug resistance because antimicrobial drugs are directed against conserved critical functions
Summary
Fitness loss in artemisinin-resistant parasites under amino acid starvation. In order to study fitness trade-off, artemisinin-resistant strains (ANL2 and ANL4) from Cambodia were studied in comparison to laboratory strains and drug-sensitive isolates (ANL1 and ANL3) collected during the same period[10]. Association between SNPs at haemoglobin processing genes and parasite clearance time following artemisinin treatment. It functions as a broad-spectrum aminopeptidase in the food vacuole that releases amino acid from the N-termini of oligopeptides[28,29]. The G223R mutation in the gene encoding Plasmepsin III (PM3) was associated with fast artemisinin clearance with the p-value of 5.8 × 10−14 (the 99.9th percentile) (Table 1) This residue is located at the entry of the active site cleft, and the conversion from glycine to arginine is likely to affect substrate accessibility. It does not exclude the important of the SNPs listed in Supplementary Table 1)
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