HDQ, a Potent Inhibitor of Plasmodium falciparum Proliferation, Binds to the Quinone Reduction Site of the Cytochrome bc 1 Complex - Archive ouverte HAL
Article Dans Une Revue Antimicrobial Agents and Chemotherapy Année : 2012

HDQ, a Potent Inhibitor of Plasmodium falciparum Proliferation, Binds to the Quinone Reduction Site of the Cytochrome bc 1 Complex

Résumé

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(1 H )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.

Dates et versions

hal-03470770 , version 1 (08-12-2021)

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Citer

Cindy Vallières, Nicholas Fisher, Thomas Antoine, Mohammed Al-Helal, Paul Stocks, et al.. HDQ, a Potent Inhibitor of Plasmodium falciparum Proliferation, Binds to the Quinone Reduction Site of the Cytochrome bc 1 Complex. Antimicrobial Agents and Chemotherapy, 2012, 56 (7), pp.3739-3747. ⟨10.1128/AAC.00486-12⟩. ⟨hal-03470770⟩
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