Malaria parasites can develop stable resistance to artemisinin but lack mutations in candidate genes atp6 (encoding the sarcoplasmic and endoplasmic reticulum Ca2+ ATPase), tctp, mdr1, and cg10.
Resistance of Plasmodium falciparum to drugs such as chloroquine and sulfadoxine-pyrimethamine is a major problem in malaria control. Artemisinin (ART) derivatives, particularly in combination with other drugs, are thus increasingly used to treat malaria, reducing the probability that parasites resistant to the components will emerge. Although stable resistance to artemisinin has yet to be reported from laboratory or field studies, its emergence would be disastrous because of the lack of alternative treatments. Here, we report for the first time, to our knowledge, genetically stable and transmissible ART and artesunate (ATN)-resistant malaria parasites. Each of two lines of the rodent malaria parasite Plosmodium chabaudi chabaudi, grown in the presence of increasing concentrations of ART or ATN, showed 15-fold and 6-fold increased resistance to ART and ATN, respectively. Resistance remained stable after cloning, freeze-thawing, after passage in the absence of drug, and transmission through mosquitoes. The nucleotide sequences of the possible genetic modulators of ART resistance (mdr1, cg10, tctp, and atp6) of sensitive and resistant parasites were compared. No mutations in these genes were identified. In addition we investigated whether changes in the copy number of these genes could account for resistance but found that resistant parasites retained the same number of copies as their sensitive progenitors. We believe that this is the first report of a malaria parasite with genetically stable and transmissible resistance to artemisinin or its derivatives.
Afonso
A
A
Centro de Malaria e Outras Doenças Tropicais/IHMT/UEI Malaria, Rua da Junqueira 96, 1349-008 Lisbon, Portugal.
Hunt
P
P
Cheesman
S
S
Alves
A C
AC
Cunha
C V
CV
do Rosário
V
V
Cravo
P
P
D000595:Amino Acid Sequence; D000818:Animals; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D014408:Biomarkers, Tumor / Q000235:genetics*; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D004351:Drug Resistance; D005260:Female; D018628:Gene Dosage; D019450:Genes, MDR; D017125:Genes, Protozoan; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D016788:Plasmodium chabaudi / Q000187:drug effects* / Q000235:genetics; D012717:Sesquiterpenes / Q000494:pharmacology*; D000090324:Tumor Protein, Translationally-Controlled 1
C513500:ATP6 protein, Plasmodium falciparum; D037621:Artemisinins; D014408:Biomarkers, Tumor; D012717:Sesquiterpenes; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; D000077332:Artesunate; C031327:artemisinin; D000252:Calcium-Transporting ATPases