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Mechanisms of in vitro resistance to dihydroartemisinin in Plasmodium falciparum
- Publication Year :
- 2012
-
Abstract
- The recent reports of artemisinin (ART) resistance in the Thai-Cambodian border area raise a serious concern on the long-term efficacy of ARTs. To elucidate the resistance mechanisms, we performed in vitro selection with dihydroartemisinin (DHA) and obtained two parasite clones from Dd2 with more than 25-fold decrease in susceptibility to DHA. The DHA-resistant clones were more tolerant of stressful growth conditions and more resistant to several commonly used antimalarial drugs than Dd2. The result is worrisome since many of the drugs are currently used as ART partners in malaria control. This study showed that the DHA resistance is not limited to ring stage, but also occurred in trophozoites and schizonts. Microarray and biochemical analyses revealed pfmdr1 amplification, elevation of the antioxidant defense network, and increased expression of many chaperones in the DHA-resistant parasites. Without drug pressure, the DHA resistant parasites reverted to sensitive in approximately eight weeks, accompanied by de-amplification of pfmdr1 and reduced antioxidant activities. The parallel decrease and increase in pfmdr1 copy number and antioxidant activity and the up and down of DHA sensitivity strongly suggest that pfmdr1 and antioxidant defense play a role in in vitro resistance to DHA, providing potential molecular markers for ART resistance.
- Subjects :
- Gene Expression Profiling
Plasmodium falciparum
Drug Resistance
Gene Dosage
food and beverages
Microarray Analysis
Article
Artemisinins
Antimalarials
Stress, Physiological
parasitic diseases
lipids (amino acids, peptides, and proteins)
Multidrug Resistance-Associated Proteins
Selection, Genetic
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.pmid..........93f0148d511f6b220f5e27dddd86bc37