The rapid development and spread of drug resistant
Plasmodium falciparum is a serious global health problem in the management of malaria infections. Increasing resistance to antimalarials by
P. falciparum has led to renewed search for alternative effective new drugs with unique cellular targets. In the 1990s, the urgent need for new anti-malarial drugs for treatment and chemoprophylaxis led to the development of atovaquone (2-[
trans-4-(4'-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-hydroxynaphtoquinone)[
1]. This anti-malarial compound has broad spectrum activity against human protozoan pathogens [
2,
3] among which are the
Plasmodium spp. [
4,
5]. Atovaquone is a potent and specific inhibitor of the cytochrome
bc 1 (
cytbc1) complex [
6,
7], an essential respiratory enzyme present in the inner mitochondrial membrane. Unfortunately, in the
Plasmodium genus and especially in
P. falciparum, atovaquone when used as a single agent showed a high frequency of recrudescence [
8,
9] and recrudescing parasites are approximately 1,000–10,000 fold more resistant [
10‐
12]. In order to minimize the risk of resistance development, a fixed synergistic combination of atovaquone with proguanil hydrochloride was developed under the trade name of Malarone
®. It has been suggested that proguanil at lower doses acts synergistically to enhance the ability of atovaquone to collapse the mitochondrial membrane potential without affecting electron transport inhibition [
13]. However, the exact mechanism of synergy between these two drugs remains unknown. The combination of atovaquone-proguanil (AP) can achieve a cure rate of 99%–100% [
9,
14‐
16]. Despite its high activity against the malaria parasite, the cost of AP treatment has until now restricted its use to western non-immune adult and children [
17] travelers and some European military personnel [
18]. Unfortunately, there is growing evidence that malaria parasites may quickly develop resistance to AP by mutation of amino acid residues located in or near the atovaquone-binding site on
cytb [
19‐
23]. Only a decade after its introduction, AP treatment failures have been reported in non-immune travelers returning from Africa. Nearly all cases are from individuals who have visited West Africa. [
11,
22,
24‐
27]. AP treatment failures in a significant number of these patients have been genetically linked to point mutations in the atovaquone-binding site of the
P. falciparum mitochondrial
cytb gene(Tyr268Ser or Tyr268Asn or Tyr268Cys) [
11,
12,
22,
24‐
28].
Recently, Kessl and colleagues [
7] used site directed mutagenesis in
Saccharomyces cerevisiae to genetically and biochemically confirm the linkage of atovaquone/AP resistance to
cytb mutations (Tyr268Ser and Tyr268Asn) and to explain at the molecular level the mechanism of malaria parasites resistance to this drug.
Cytb Tyr268Ser and Tyr268Asn mutations, have been used as a potential molecular marker of AP resistance in non-immune travelers who present with malaria after visiting disease endemic areas [
11,
12,
22,
24‐
30].
It has been suggested that AP resistant phenotypes might arise through strong selection of resistant sub-populations harboring resistance associated mutations [
12,
29] or, through a mutagenic capacity of atovaquone on
P. falciparum parasites alone or even in the AP combination [
19,
20,
25] However, very little is known on the background/baseline prevalence of codon-268 mutations in natural populations of
P. falciparum without previous exposure to the drug in Africa. In this study, the prevalence of codon-268 mutations in the
cytb gene of
P. falciparum isolates from Nigeria, Malawi and Senegal was assessed.