Abstract
BackgroundAnti-malarial drug resistance has emerged as one of the biggest challenges confronting the worldwide effort to control malaria. The appearance of chloroquine and multi-drug resistance had devastating effects on therapeutic efficacy of former first-line agents. Artemisinin has proven to be an excellent therapeutic alternative to fill the void in chemotherapeutic options left by resistance mechanisms. At the time of introduction, no resistance to artemisinins had been recorded, and artemisinins demonstrated excellent parasite reduction rates. In an attempt to protect artemisinin efficacy, the World Health Organization (WHO) made artemisinin-based combination therapy (ACT) its official first-line treatment recommendation for uncomplicated Plasmodium falciparum in 2006. In Brazil, artemether/lumefantrine became the Brazilian Malaria Control Programme's official treatment recommendation in 2007. The sarco/endoplasmic reticulum Ca2+ - ATPase ortholog of P. falciparum (pfatp6) has been suggested as one of the targets of artemisinins. Consequently, pfatp6 gene polymorphisms are being investigated as markers of artemisinin resistance elsewhere. The goal of this work was to describe the molecular profile of pfatp6 in P. falciparum isolates from different localities in the Amazonas State.MethodsDNA polymorphisms of the pfatp6 gene in 80 P. falciparum isolates from 11 municipalities of the Amazonas State (Western Brazilian Amazon), before and after the introduction of ACT in the Brazilian anti-malarial guidelines, were analysed by automatic sequencing. Mutations in the pfatp6 gene were searched using Mutation Surveyor v3.25 software.ResultsThe P. falciparum pfatp6 gene presented polymorphisms at codons 37, 630 and 898. The R37K mutation was found in 16% of the samples, A630S in 32% and I898I in 52%. No S769N mutation, however, was detected in the analysed samples.ConclusionDespite the small number of samples, data presented here provide baseline information about polymorphisms of pfatp6 gene before and after exposure to ACT in a low transmission area, which will help to infer drug selection pressure in this area in the future.
Highlights
Anti-malarial drug resistance has emerged as one of the biggest challenges confronting the worldwide effort to control malaria
The Brazilian Amazon Region is responsible for 99.8% of all reported malarial cases in the Brazil, where socioeconomic and environmental conditions favor the proliferation of the Anopheles darlingi mosquito
This study reports pfatp6 gene polymorphisms in P. falciparum isolates collected before and after the introduction of artemisinin-based combination therapy (ACT) in eleven endemic municipalities
Summary
Anti-malarial drug resistance has emerged as one of the biggest challenges confronting the worldwide effort to control malaria. In the State of Amazonas, where this study was conducted, 32,566 cases were reported from January to July in 2010, Plasmodium falciparum resistance to anti-malarial drugs, especially chloroquine and pyrimethamine-sulphadoxine, has emerged as one of the biggest challenges to be faced in malaria control [2]. Artemisinin-based combination therapy (ACT) is the WHO recommended strategy for preventing the development of drug resistance, and, in Brazil, artemether-lumefantrine was subsequently adopted by the Brazilian Ministry of Health’s first-line treatment recommendation for uncomplicated falciparum infections. The efficacy of this strategy, has become threatened by the discovery of delayed artemisinin sensitivity on the ThaiCambodian border [3]. A previous study, with P. falciparum suggested that a sarcoplasmic and endoplasmic reticulum Ca2 +-ATPase (SERCA)-type protein encoded by the gene pfatp might be the primary target of these drugs [5] (Figure 1), and mutations in this gene may alter P. falciparum’s sensitivity to artemisinin
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