title: A chemical genomic analysis of decoquinate, a Plasmodium falciparum cytochrome b inhibitor.
abstract: Decoquinate has single-digit nanomolar activity against in vitro blood stage Plasmodium falciparum parasites, the causative agent of human malaria. In vitro evolution of decoquinate-resistant parasites and subsequent comparative genomic analysis to the drug-sensitive parental strain revealed resistance was conferred by two nonsynonymous single nucleotide polymorphisms in the gene encoding cytochrome b. The resultant amino acid mutations, A122T and Y126C, reside within helix C in the ubiquinol-binding pocket of cytochrome b, an essential subunit of the cytochrome bc(1) complex. As with other cytochrome bc(1) inhibitors, such as atovaquone, decoquinate has low nanomolar activity against in vitro liver stage P. yoelii and provides partial prophylaxis protection when administered to infected mice at 50 mg kg(-1). In addition, transgenic parasites expressing yeast dihydroorotate dehydrogenase are >200-fold less sensitive to decoquinate, which provides additional evidence that this drug inhibits the parasite's mitochondrial electron transport chain. Importantly, decoquinate exhibits limited cross-resistance to a panel of atovaquone-resistant parasites evolved to harbor various mutations in cytochrome b. The basis for this difference was revealed by molecular docking studies, in which both of these inhibitors were shown to have distinctly different modes of binding within the ubiquinol-binding site of cytochrome b.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Tae-Gyu
authors.initials: TG
authors.lastname: Nam
authors.forename: Case W
authors.initials: CW
authors.lastname: McNamara
authors.forename: Selina
authors.initials: S
authors.lastname: Bopp
authors.forename: Neekesh V
authors.initials: NV
authors.lastname: Dharia
authors.forename: Stephan
authors.initials: S
authors.lastname: Meister
authors.forename: Ghislain M C
authors.initials: GM
authors.lastname: Bonamy
authors.forename: David M
authors.initials: DM
authors.lastname: Plouffe
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kato
authors.forename: Susan
authors.initials: S
authors.lastname: McCormack
authors.forename: Badry
authors.initials: B
authors.lastname: Bursulaya
authors.forename: Hangjun
authors.initials: H
authors.lastname: Ke
authors.forename: Akhil B
authors.initials: AB
authors.lastname: Vaidya
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D045303:Cytochromes b / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003667:Decoquinate / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D025141:Drug Resistance, Fungal / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D003667:Decoquinate; D045303:Cytochromes b