ArticleAntimicrobial agents and chemotherapy2012
HDQ, a potent inhibitor of Plasmodium falciparum proliferation, binds to the quinone reduction site of the cytochrome bc1 complex.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed.
- Article
- Revisiting 2-Substituted-4(1Journal of medicinal chemistry · 2026Article
- STOP Strategy to InhibitAntibiotics (Basel, Switzerland) · 2025Article
- Inhibitors of Type II NADH Dehydrogenase Enzyme: A Review.Current protein & peptide science · 2025Review
- Inhibitors of Type II NADH Dehydrogenase Enzyme: A Review.Current protein & peptide science · 2025Review
- A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites.PLoS pathogens · 2023Article
- Structure-activity relationships ofExpert opinion on drug discovery · 2022Article
- Acridones Are Highly Potent Inhibitors ofACS infectious diseases · 2021Article
- PfMFR3: A Multidrug-Resistant Modulator inACS infectious diseases · 2021Article
- Catalytic Reactions and Energy Conservation in the CytochromeChemical reviews · 2021Review
- Mitochondrial type II NADH dehydrogenase of Plasmodium falciparum (PfNDH2) is dispensable in the asexual blood stages.PloS one · 2019Article
- Targeted Structure-Activity Analysis of Endochin-like Quinolones Reveals Potent Qi and Qo Site Inhibitors of Toxoplasma gondii and Plasmodium falciparum Cytochrome bcACS infectious diseases · 2018Article
- Selection ofProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Using in Vitro Evolution and Whole Genome Analysis To Discover Next Generation Targets for Antimalarial Drug Discovery.ACS infectious diseases · 2018Review
- Characterization of the mechanism of action of the fungicide fenpicoxamid and its metabolite UK-2A.Pest management science · 2018Article
- Targeting Channels and Transporters in Protozoan Parasite Infections.Frontiers in chemistry · 2018Review
- Synergy and Target Promiscuity Drive Structural Divergence in Bacterial Alkylquinolone Biosynthesis.Cell chemical biology · 2017Article
- The Candidate Antimalarial Drug MMV665909 Causes Oxygen-Dependent mRNA Mistranslation and Synergizes with Quinoline-Derived Antimalarials.Antimicrobial agents and chemotherapy · 2017Article
- Genetic Evidence for Cytochrome b Qi Site Inhibition by 4(1H)-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii.Antimicrobial agents and chemotherapy · 2017Article
- Drugs in development for toxoplasmosis: advances, challenges, and current status.Drug design, development and therapy · 2017Review
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11 authors.
Funding
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.
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