Mechanisms of in vitro resistance to dihydroartemisinin in Plasmodium falciparum

Long Cui, Zenglei Wang, Jun Miao, Miao Miao, Ramesh Chandra, Hongying Jiang, Xin Zhuan Su, Liwang Cui

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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 as 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 defence network, and increased expression of many chaperones in the DHA-resistant parasites. Without drug pressure, the DHA-resistant parasites reverted to sensitivity in approximately 8 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 defence play a role in in vitro resistance to DHA, providing potential molecular markers for ART resistance.

Original languageEnglish (US)
Pages (from-to)111-128
Number of pages18
JournalMolecular Microbiology
Volume86
Issue number1
DOIs
StatePublished - Oct 1 2012

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All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

Cite this

Cui, L., Wang, Z., Miao, J., Miao, M., Chandra, R., Jiang, H., Su, X. Z., & Cui, L. (2012). Mechanisms of in vitro resistance to dihydroartemisinin in Plasmodium falciparum. Molecular Microbiology, 86(1), 111-128. https://doi.org/10.1111/j.1365-2958.2012.08180.x