Molecular surveillance of mutations in the cytochrome b gene of Plasmodium falciparum in Gabon and Ethiopia

Tamirat Gebru,Peter G Kremsner,Jürgen Fj Kun,Asrat Hailu,Martin P Grobusch

doi:10.1186/1475-2875-5-112

Tamirat Gebru, Peter G Kremsner + Show 3 more

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https://doi.org/10.1186/1475-2875-5-112

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BackgroundAtovaquone is part of the antimalarial drug combination atovaquone-proguanil (Malarone®) and inhibits the cytochrome bc1 complex of the electron transport chain in Plasmodium spp. Molecular modelling showed that amino acid mutations are clustered around a putative atovaquone-binding site resulting in a reduced binding affinity of atovaquone for plasmodial cytochrome b, thus resulting in drug resistance.MethodsThe prevalence of cytochrome b point mutations possibly conferring atovaquone resistance in Plasmodium falciparum isolates in atovaquone treatment-naïve patient cohorts from Lambaréné, Gabon and from South Western Ethiopia was assessed.ResultsFour/40 (10%) mutant types (four different single polymorphisms, one leading to an amino acid change from M to I in a single case) in Gabonese isolates, but all 141/141 isolates were wild type in Ethiopia were found.ConclusionIn the absence of drug pressure, spontaneous and possibly resistance-conferring mutations are rare.

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Atovaquone is part of the antimalarial drug combination atovaquone-proguanil (Malarone®) and inhibits the cytochrome bc1 complex of the electron transport chain in Plasmodium spp
By binding to the cytochrome bc1 complex of the parasite, atovaquone, which was introduced in a fixed combination with proguanil hydrochloride as an antimalarial drug in the late 1990s [3], leads to the collapse of the mitochondrial membrane potential at far lower concentrations than that at which the respective mammalian system is affected [4,5]
Single nucleotide polymorphisms: T676A, C689T; T760G and G925T were detected in the Gabonese samples

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Introduction

Atovaquone is part of the antimalarial drug combination atovaquone-proguanil (Malarone®) and inhibits the cytochrome bc complex of the electron transport chain in Plasmodium spp. The genetic complexity of Plasmodium falciparum and its ability to generate mutant variants in particular makes it a strikingly successful pathogen. P. falciparum undergoes mutations in respective target genes, resulting in variations of the encoded proteins which facilitate escape from particular antimalarial compounds. By binding to the cytochrome bc complex of the parasite, atovaquone, which was introduced in a fixed combination with proguanil hydrochloride as an antimalarial drug in the late 1990s [3], leads to the collapse of the mitochondrial membrane potential at far lower concentrations than that at which the respective mammalian system is affected [4,5]. Its mode of action is unique in targeting parasite (page number not for citation purposes)

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