MALARIA: Molecular Markers to identify drug resistance

Effective monitoring strategies are needed to reduce the malaria burden in tropical and subtropical areas. Molecular markers for drug resistance represent a great tool for evaluating drug efficacy and guiding treatment policy. Molecular markers for resistance are based on genetic changes that confer parasite resistance to drugs. To date, their validation process had been slow and their application as surveillance of resistance has been limited.
Development and Validation of Molecular Markers for Resistance
In the late 20th century, candidate molecular markers for antimalarial drug resistance were identified by cloning and sequencing parasite homologues of genes that mediate resistance in other organisms and by using reverse genetics approaches to analyse the progeny of genetic crosses between sensitive and resistant parasites.
Differences in DNA sequence or gene expression between sensitive and resistant parasites were described, and point mutations, differences in length repeat sequences or copy number were evaluated for associations with in vitro resistance phenotypes.
Finally, molecular markers for resistance were assessed in ecological studies and clinical trials to establish their association with treatment outcome in vivo. Other factors such as acquired immunity and pharmacokinetics influence the clearance of the parasite rendering challenging the evaluation of molecular markers.
Molecular Markers for Resistance to Monotherapy
Until recently, conventional drugs to treat malaria were chloroquine and the antifolates, sulphadoxine and pyrimethamine. Unfortunately, reliable markers for chloroquine and sulphadoxine-pyrimethamine (SP) resistance were established only after resistance to these drugs was widespread.

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Chloroquine resistance has been linked to polymorphisms in the chloroquine resistance transporter (PfCRT), and mutations in the P-glycoprotein homologue (Pgh1) encoded by pfmdr1 modulate this resistance. Pyrimethamine resistance is conferred by polymorphisms in the parasite dihydrofolate reductase (DHFR) and polymorphisms in dihydropteroate synthase (DHPS) cause resistance to sulphadoxine.
Application of Resistance Markers
Routine assessment of drug resistance using molecular markers is not yet a reality and only a few molecular surveys have been conducted. Nevertheless, the direct practical value of molecular surveys came from outbreak of malaria in 1999 in Mali. Molecular assays for markers predictive of resistance to chloroquine and SP suggested an unexpectedly high prevalence of resistance to chloroquine, but not to SP. Consequently, the population was effectively treated with SP. Another example came from Tanzania where molecular markers for resistance had been used to guide national treatment policy.
Resistance markers have also predicted the return of susceptible parasites after the removal of drug pressure. In Malawi, a decrease in the prevalence of the molecular marker for chloroquine resistance and an increase in the prevalence of SP markers were detected soon after the country switched from chloroquine to SP for the first line therapy of malaria. These data were confirmed by a clinical trial showing a dramatic increase in chloroquine efficacy an equally dramatic decrease in SP efficacy.
Molecular Markers for Resistance in the ACT Era
In the era of artemisinin-based combination therapies (ACTs), tracking resistance will be crucial to prolong the therapeutic lives of these new drugs. ACT associate artemisinins with other antimalarials such as amodiaquine, lumefantrine, and piperaquine. To date, the molecular basis for their resistance is not well established. Recent advances in genomic technologies should help identifying and validating markers as soon as resistance emerges.Read more at Suite101: Malaria: Molecular Markers for Drug Resistant Falciparum parasite http://biotechpharmaceuticals.suite101.com/article.cfm/malaria-molecular-markers-for-drug-resistant-falciparum-parasite#ixzz0oqYN4rbd