Mutation underlying resistance of Plasmodium berghei to atovaquone in the quinone binding domain 2 (Qo2) of the cytochrome b gene

The anti-malarial agent atovaquone specifically targets the cytochrome bc1 complex and inhibits the parasite respiration. Resistance to this drug, a coenzyme Q analogue, is associated with mutations in the mitochondrial cytochrome b gene. We previously reported atovaquone resistant mutations in Plasmodium berghei, in the first quinone binding domain (Qo1) of the cytochrome b gene (M133I and L144S) with V284F in the sixth transmembrane domain. However, in P. falciparum the most common mutations are found in the Qo2 region. To obtain a better model for biochemical and genetic studies, we have now extended our study to isolate a wider range of P. berghei resistant strains, in particular those in the Qo2. Here we report four new mutations (Y268N, Y268C, L271V and K272R), all in the Qo2 domain. Two of these mutations are convergent to codon 268 (nt802–804) drug-induced mutation in P. falciparum.