title: Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site.
abstract: Atovaquone is the major active component of the new antimalarial drug Malarone. Considerable evidence suggests that malaria parasites become resistant to atovaquone quickly if atovaquone is used as a sole agent. The mechanism by which the parasite develops resistance to atovaquone is not yet fully understood. Atovaquone has been shown to inhibit the cytochrome bc(1) (CYT bc(1)) complex of the electron transport chain of malaria parasites. Here we report point mutations in Plasmodium falciparum CYT b that are associated with atovaquone resistance. Single or double amino acid mutations were detected from parasites that originated from a cloned line and survived various concentrations of atovaquone in vitro. A single amino acid mutation was detected in parasites isolated from a recrudescent patient following atovaquone treatment. These mutations are associated with a 25- to 9,354-fold range reduction in parasite susceptibility to atovaquone. Molecular modeling showed that amino acid mutations associated with atovaquone resistance are clustered around a putative atovaquone-binding site. Mutations in these positions are consistent with a reduced binding affinity of atovaquone for malaria parasite CYT b.
authors.affiliation: Parasitology and Arbovirology Department, Australian Army Malaria Institute, University of Queensland, St. Lucia, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Korsinczky
authors.forename: N
authors.initials: N
authors.lastname: Chen
authors.forename: B
authors.initials: B
authors.lastname: Kotecka
authors.forename: A
authors.initials: A
authors.lastname: Saul
authors.forename: K
authors.initials: K
authors.lastname: Rieckmann
authors.forename: Q
authors.initials: Q
authors.lastname: Cheng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone; D001665:Binding Sites / Q000235:genetics; D002417:Cattle; D002645:Chickens; D017124:Conserved Sequence / Q000235:genetics; D003573:Cytochrome b Group / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics; D056890:Eukaryota / Q000187:drug effects; D008689:Methacrylates; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009285:Naphthoquinones / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D011090:Polyenes / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D003573:Cytochrome b Group; D008689:Methacrylates; D009285:Naphthoquinones; D011090:Polyenes; D013844:Thiazoles; C030517:myxothiazol; C041573:stigmatellin; D053626:Atovaquone