title: Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes.
abstract: Drug resistance compromises control of malaria. Here, we show that resistance to a commonly used antimalarial medication, atovaquone, is apparently unable to spread. Atovaquone pressure selects parasites with mutations in cytochrome b, a respiratory protein with low but essential activity in the mammalian blood phase of the parasite life cycle. Resistance mutations rescue parasites from the drug but later prove lethal in the mosquito phase, where parasites require full respiration. Unable to respire efficiently, resistant parasites fail to complete mosquito development, arresting their life cycle. Because cytochrome b is encoded by the maternally inherited parasite mitochondrion, even outcrossing with wild-type strains cannot facilitate spread of resistance. Lack of transmission suggests that resistance will be unable to spread in the field, greatly enhancing the utility of atovaquone in malaria control.
authors.affiliation: School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia. gim@unimelb.edu.au deang@unimelb.edu.au.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Goodman
authors.affiliation: School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia. Eijkman Institute for Molecular Biology, JI Diponegoro no. 69, Jakarta, 10430, Indonesia. Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Josephine E
authors.initials: JE
authors.lastname: Siregar
authors.affiliation: School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Mollard
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology, Malaria Research Institute, Baltimore, MD 21205, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Vega-Rodríguez
authors.affiliation: Eijkman Institute for Molecular Biology, JI Diponegoro no. 69, Jakarta, 10430, Indonesia. Department of Parasitology, Faculty of Medicine, Hasanuddin University, Jalan Perintis Kemerdekaan Km10, Makassar 90245, Indonesia.
authors.forename: Din
authors.initials: D
authors.lastname: Syafruddin
authors.affiliation: Division of Medical Zoology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsuoka
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Motomichi
authors.initials: M
authors.lastname: Matsuzaki
authors.affiliation: School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyama
authors.affiliation: School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Angelika
authors.initials: A
authors.lastname: Sturm
authors.affiliation: School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Anton
authors.initials: A
authors.lastname: Cozijnsen
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology, Malaria Research Institute, Baltimore, MD 21205, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Jacobs-Lorena
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. School of Tropical Medicine and Global Health, Nagasaki University, Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
authors.affiliation: Eijkman Institute for Molecular Biology, JI Diponegoro no. 69, Jakarta, 10430, Indonesia.
authors.forename: Sangkot
authors.initials: S
authors.lastname: Marzuki
authors.affiliation: School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia. gim@unimelb.edu.au deang@unimelb.edu.au.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: McFadden
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology*; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D053626:Atovaquone / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D045303:Cytochromes b / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D050259:Genes, Mitochondrial / Q000235:genetics; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects / Q000235:genetics; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology* / Q000635:transmission; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation; D010962:Plasmodium berghei / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D012641:Selection, Genetic
chemical_list: D000962:Antimalarials; D045303:Cytochromes b; D053626:Atovaquone