HDQ, a Potent Inhibitor of Plasmodium falciparum Proliferation, Binds to the Quinone Reduction Site of the Cytochromebc1Complex
ABSTRACTThe mitochondrialbc1complex is a multisubunit enzyme that catalyzes the transfer of electrons from ubiquinol to cytochromeccoupled to the vectorial translocation of protons across the inner mitochondrial membrane. The complex contains two distinct quinone-binding sites, the quinol oxidation site of thebc1complex (Qo) and the quinone reduction site (Qi), located on opposite sides of the membrane within cytochromeb. Inhibitors of the Qosite such as atovaquone, active against thebc1complex ofPlasmodium falciparum, have been developed and formulated as antimalarial drugs. Unfortunately, single point mutations in the Qosite 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 ofP. falciparumproliferation, 1-hydroxy-2-dodecyl-4(1H)quinolone (HDQ). We show that the parasitebc1complex—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 Qisite, namely, G33A, H204Y, M221Q, and K228M, markedly decreased HDQ inhibition. In contrast, known inhibitor resistance mutations at the Qosite did not cause HDQ resistance. This study, using HDQ as a proof-of-principle inhibitor, indicates that the Qisite of thebc1complex is a viable target for antimalarial drug development.