HDQ, a Potent Inhibitor of Plasmodium falciparum Proliferation, Binds to the Quinone Reduction Site of the Cytochrome bc 1 Complex
| Autor: | Brigitte Meunier, Thomas Antoine, Mohammed Al-Helal, Nicholas Fisher, Alexandre S. Lawrenson, Paul A. Stocks, Cindy Vallières, Neil G. Berry, Stephen A. Ward, Giancarlo A. Biagini, Paul M. O'Neill |
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| Přispěvatelé: | Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Liverpool School of Tropical Medicine (LSTM), University of Liverpool |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Ubiquinol
Cytochrome Stereochemistry [SDV]Life Sciences [q-bio] Plasmodium falciparum Quinolones 03 medical and health sciences chemistry.chemical_compound Antimalarials Electron Transport Complex III Mechanisms of Resistance medicine Pharmacology (medical) Binding site Inner mitochondrial membrane 030304 developmental biology Pharmacology 0303 health sciences Binding Sites biology 030306 microbiology Cytochrome c biology.organism_classification 3. Good health Infectious Diseases chemistry Coenzyme Q – cytochrome c reductase biology.protein Atovaquone medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2012, 56 (7), pp.3739-3747. ⟨10.1128/AAC.00486-12⟩ |
| ISSN: | 0066-4804 1098-6596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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