In vitro sensitivity of plasmodium falciparum from China-Myanmar border area to major ACT drugs and polymorphisms in potential target genes

Zenglei Wang, Daniel Parker, Hao Meng, Lanou Wu, Jia Li, Zhen Zhao, Rongping Zhang, Qi Fan, Haiyan Wang, Liwang Cui, Zhaoqing Yang

Research output: Contribution to journalArticle

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Abstract

Drug resistance has always been one of the most important impediments to global malaria control. Artemisinin resistance has recently been confirmed in the Greater Mekong Subregion (GMS) and efforts for surveillance and containment are intensified. To determine potential mechanisms of artemisinin resistance and monitor the emergence and spread of resistance in other regions of the GMS, we investigated the in vitro sensitivity of 51 culture-adapted parasite isolates from the China-Myanmar border area to four drugs. The 50% inhibitory concentrations (IC50s) of dihydroartemisinin, mefloquine and lumefantrine were clustered in a relatively narrow, 3- to 6-fold range, whereas the IC50 range of artesunate was 12-fold. We assessed the polymorphisms of candidate resistance genes pfcrt, pfmdr1, pfATP6, pfmdr6 and pfMT (a putative metabolite/drug transporter). The K76T mutation in pfcrt reached fixation in the study parasite population, whereas point mutations in pfmdr1 and pfATP6 had low levels of prevalence. In addition, pfmdr1 gene amplification was not detected. None of the mutations in pfmdr1 and pfATP6 was associated significantly with in vitro sensitivity to artemisinin derivatives. The ABC transporter gene pfmdr6 harbored two point mutations, two indels, and number variations in three simple repeats. Only the length variation in a microsatellite repeat appeared associated with altered sensitivity to dihydroartemisinin. The PfMT gene had two point mutations and one codon deletion; the I30N and N496- both reached high levels of prevalence. However, none of the SNPs or haplotypes in PfMT were correlated significantly with resistance to the four tested drugs. Compared with other parasite populations from the GMS, our studies revealed drastically different genotype and drug sensitivity profiles in parasites from the China-Myanmar border area, where artemisinins have been deployed extensively for over 30 years.

Original languageEnglish (US)
Article numbere30927
JournalPloS one
Volume7
Issue number5
DOIs
StatePublished - May 31 2012

Fingerprint

Myanmar
artemisinin
dihydroartemisinin
Plasmodium falciparum
Polymorphism
China
Parasites
point mutation
Genes
Point Mutation
genetic polymorphism
parasites
drugs
Pharmaceutical Preparations
Inhibitory Concentration 50
inhibitory concentration 50
Artemisinins
genes
Malaria control
Mefloquine

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Wang, Zenglei ; Parker, Daniel ; Meng, Hao ; Wu, Lanou ; Li, Jia ; Zhao, Zhen ; Zhang, Rongping ; Fan, Qi ; Wang, Haiyan ; Cui, Liwang ; Yang, Zhaoqing. / In vitro sensitivity of plasmodium falciparum from China-Myanmar border area to major ACT drugs and polymorphisms in potential target genes. In: PloS one. 2012 ; Vol. 7, No. 5.
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abstract = "Drug resistance has always been one of the most important impediments to global malaria control. Artemisinin resistance has recently been confirmed in the Greater Mekong Subregion (GMS) and efforts for surveillance and containment are intensified. To determine potential mechanisms of artemisinin resistance and monitor the emergence and spread of resistance in other regions of the GMS, we investigated the in vitro sensitivity of 51 culture-adapted parasite isolates from the China-Myanmar border area to four drugs. The 50{\%} inhibitory concentrations (IC50s) of dihydroartemisinin, mefloquine and lumefantrine were clustered in a relatively narrow, 3- to 6-fold range, whereas the IC50 range of artesunate was 12-fold. We assessed the polymorphisms of candidate resistance genes pfcrt, pfmdr1, pfATP6, pfmdr6 and pfMT (a putative metabolite/drug transporter). The K76T mutation in pfcrt reached fixation in the study parasite population, whereas point mutations in pfmdr1 and pfATP6 had low levels of prevalence. In addition, pfmdr1 gene amplification was not detected. None of the mutations in pfmdr1 and pfATP6 was associated significantly with in vitro sensitivity to artemisinin derivatives. The ABC transporter gene pfmdr6 harbored two point mutations, two indels, and number variations in three simple repeats. Only the length variation in a microsatellite repeat appeared associated with altered sensitivity to dihydroartemisinin. The PfMT gene had two point mutations and one codon deletion; the I30N and N496- both reached high levels of prevalence. However, none of the SNPs or haplotypes in PfMT were correlated significantly with resistance to the four tested drugs. Compared with other parasite populations from the GMS, our studies revealed drastically different genotype and drug sensitivity profiles in parasites from the China-Myanmar border area, where artemisinins have been deployed extensively for over 30 years.",
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Wang, Z, Parker, D, Meng, H, Wu, L, Li, J, Zhao, Z, Zhang, R, Fan, Q, Wang, H, Cui, L & Yang, Z 2012, 'In vitro sensitivity of plasmodium falciparum from China-Myanmar border area to major ACT drugs and polymorphisms in potential target genes', PloS one, vol. 7, no. 5, e30927. https://doi.org/10.1371/journal.pone.0030927

In vitro sensitivity of plasmodium falciparum from China-Myanmar border area to major ACT drugs and polymorphisms in potential target genes. / Wang, Zenglei; Parker, Daniel; Meng, Hao; Wu, Lanou; Li, Jia; Zhao, Zhen; Zhang, Rongping; Fan, Qi; Wang, Haiyan; Cui, Liwang; Yang, Zhaoqing.

In: PloS one, Vol. 7, No. 5, e30927, 31.05.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - In vitro sensitivity of plasmodium falciparum from China-Myanmar border area to major ACT drugs and polymorphisms in potential target genes

AU - Wang, Zenglei

AU - Parker, Daniel

AU - Meng, Hao

AU - Wu, Lanou

AU - Li, Jia

AU - Zhao, Zhen

AU - Zhang, Rongping

AU - Fan, Qi

AU - Wang, Haiyan

AU - Cui, Liwang

AU - Yang, Zhaoqing

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