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.
Highlights
The development and spread of multidrug resistant (MDR) Plasmodium falciparum has led to the adoption of artemisinin-based combination therapies (ACTs) as the first-line treatment for falciparum malaria in most malaria-endemic countries of the world [1]
In vitro Drug Assays To determine whether artemisinin resistance has emerged at the China-Myanmar border area, we assessed in vitro sensitivity of 51 culture-adapted P. falciparum strains originating from this region to two artemisinin derivatives AS and DHA and two aminoalcoholic drugs MQ and LMF
When the IC50 data were stratified by years, slight variations were observed between the years (Figure 1)
Summary
The development and spread of multidrug resistant (MDR) Plasmodium falciparum has led to the adoption of artemisinin-based combination therapies (ACTs) as the first-line treatment for falciparum malaria in most malaria-endemic countries of the world [1]. The recently confirmed emergence of artemisinin resistance in western Cambodia is a major threat for current initiatives to control and eliminate malaria [3,4,5]. Because this exact same area has been the origin of both chloroquine (CQ) and sulfadoxine-pyrimethamine resistance, both of which have subsequently spread to Africa [6,7], the consequence of a similar spread of artemisinin resistance will be catastrophic. Containment efforts require better resistance surveillance [11], but this is hampered due to the lack of convenient molecular surveillance tools for detecting artemisinin resistance. The most reliable way of detecting artemisinin resistance is through rigorous clinical efficacy studies, which are expensive and time-consuming
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