title: HDQ, a potent inhibitor of Plasmodium falciparum proliferation, binds to the quinone reduction site of the cytochrome bc1 complex.
abstract: The mitochondrial bc(1) complex is a multisubunit enzyme that catalyzes the transfer of electrons from ubiquinol to cytochrome c coupled to the vectorial translocation of protons across the inner mitochondrial membrane. The complex contains two distinct quinone-binding sites, the quinol oxidation site of the bc(1) complex (Q(o)) and the quinone reduction site (Q(i)), located on opposite sides of the membrane within cytochrome b. Inhibitors of the Q(o) site such as atovaquone, active against the bc(1) complex of Plasmodium falciparum, have been developed and formulated as antimalarial drugs. Unfortunately, single point mutations in the Q(o) site can rapidly render atovaquone ineffective. The development of drugs that could circumvent cross-resistance with atovaquone is needed. Here, we report on the mode of action of a potent inhibitor of P. falciparum proliferation, 1-hydroxy-2-dodecyl-4(1H)quinolone (HDQ). We show that the parasite bc(1) complex--from both control and atovaquone-resistant strains--is inhibited by submicromolar concentrations of HDQ, indicating that the two drugs have different targets within the complex. The binding site of HDQ was then determined by using a yeast model. Introduction of point mutations into the Q(i) site, namely, G33A, H204Y, M221Q, and K228M, markedly decreased HDQ inhibition. In contrast, known inhibitor resistance mutations at the Q(o) site did not cause HDQ resistance. This study, using HDQ as a proof-of-principle inhibitor, indicates that the Q(i) site of the bc(1) complex is a viable target for antimalarial drug development.
authors.affiliation: Centre de Génétique Moléculaire, CNRS, FRC 3115, Avenue de la Terrasse, Gif-sur-Yvette, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Vallières
authors.forename: Nicholas
authors.initials: N
authors.lastname: Fisher
authors.forename: Thomas
authors.initials: T
authors.lastname: Antoine
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Helal
authors.forename: Paul
authors.initials: P
authors.lastname: Stocks
authors.forename: Neil G
authors.initials: NG
authors.lastname: Berry
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Lawrenson
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
authors.forename: Brigitte
authors.initials: B
authors.lastname: Meunier
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D014450:Electron Transport Complex III / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C521526:1-hydroxy-2-dodecyl-4(1H)quinolone; D000962:Antimalarials; D015363:Quinolones; D014450:Electron Transport Complex III