Exploring the contribution of candidate genes to artemisinin resistance in Plasmodium falciparum.
The reduced in vivo sensitivity of Plasmodium falciparum has recently been confirmed in western Cambodia. Identifying molecular markers for artemisinin resistance is essential for monitoring the spread of the resistant phenotype and identifying the mechanisms of resistance. Four candidate genes, including the P. falciparum mdr1 (pfmdr1) gene, the P. falciparum ATPase6 (pfATPase6) gene, the 6-kb mitochondrial genome, and ubp-1, encoding a deubiquitinating enzyme, of artemisinin-resistant P. falciparum strains from western Cambodia were examined and compared to those of sensitive strains from northwestern Thailand, where the artemisinins are still very effective. The artemisinin-resistant phenotype did not correlate with pfmdr1 amplification or mutations (full-length sequencing), mutations in pfATPase6 (full-length sequencing) or the 6-kb mitochondrial genome (full-length sequencing), or ubp-1 mutations at positions 739 and 770. The P. falciparum CRT K76T mutation was present in all isolates from both study sites. The pfmdr1 copy numbers in western Cambodia were significantly lower in parasite samples obtained in 2007 than in those obtained in 2005, coinciding with a local change in drug policy replacing artesunate-mefloquine with dihydroartemisinin-piperaquine. Artemisinin resistance in western Cambodia is not linked to candidate genes, as was suggested by earlier studies.
Imwong
Mallika
M
Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Dondorp
Arjen M
AM
Nosten
Francois
F
Yi
Poravuth
P
Mungthin
Mathirut
M
Hanchana
Sarun
S
Das
Debashish
D
Phyo
Aung Phae
AP
Lwin
Khin Maung
KM
Pukrittayakamee
Sasithon
S
Lee
Sue J
SJ
Saisung
Suwannee
S
Koecharoen
Kitti
K
Nguon
Chea
C
Day
Nicholas P J
NP
Socheat
Duong
D
White
Nicholas J
NJ
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism
D000890:Anti-Infective Agents; D037621:Artemisinins; D000252:Calcium-Transporting ATPases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C513500:ATP6 protein, Plasmodium falciparum; C513498:Mdr1 protein, Plasmodium falciparum; C031327:artemisinin