Exploring Ubiquinone Biosynthesis Inhibition as a Strategy for Improving Atovaquone Efficacy in Malaria
| العنوان: | Exploring Ubiquinone Biosynthesis Inhibition as a Strategy for Improving Atovaquone Efficacy in Malaria |
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| المؤلفون: | Rodrigo A.C. Sussmann, Fernando G. de Almeida, Mauro F Azevedo, Emilia A. Kimura, H R Melo, Marcell Crispim, C A Zafra, Ignasi Bofill Verdaguer, Alejandro M. Katzin, N L Buriticá |
| المصدر: | Antimicrob Agents Chemother |
| بيانات النشر: | American Society for Microbiology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Ubiquinol, Ubiquinone, 03 medical and health sciences, chemistry.chemical_compound, Biosynthesis, medicine, Humans, Pharmacology (medical), Antimalarial Agent, IC50, Atovaquone, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, 030306 microbiology, Plasmodium falciparum, Chemistry, biology.organism_classification, Malaria, Mitochondria, Infectious Diseases, Mechanism of action, chemistry, Biochemistry, Pyrimidine metabolism, medicine.symptom, Oxidation-Reduction, medicine.drug |
| الوصف: | Atovaquone (AV) acts on the malaria parasite by competing with ubiquinol (UQH(2)) for its union to the mitochondrial bc(1) complex, preventing the ubiquinone-8 and ubiquinone-9 (UQ-8 and UQ-9) redox recycling, which is a necessary step in pyrimidine biosynthesis. This study focused on UQ biosynthesis in Plasmodium falciparum and adopted proof-of-concept research to better elucidate the mechanism of action of AV and improve its efficacy. Initially, UQ biosynthesis was evaluated using several radioactive precursors and chromatographic techniques. This methodology was suitable for studying the biosynthesis of both UQ homologs and its redox state. Additionally, the composition of UQ was investigated in parasites cultivated at different oxygen saturations or in the presence of AV. AV affected the redox states of both UQ-8 and UQ-9 homologs by increasing the levels of the respective reduced forms. Conversely, low-oxygen environments specifically inhibited UQ-9 biosynthesis and increased the antimalarial efficacy of AV. These findings encouraged us to investigate the biological importance and the potential of UQ biosynthesis as a drug target based on its inhibition by 4-nitrobenzoate (4-NB), a 4-hydroxybenzoate (4-HB) analog. 4-NB effectively inhibits UQ biosynthesis and enhances the effects of AV on parasitic growth and respiration rate. Although 4-NB itself exhibits poor antimalarial activity, its 50% inhibitory concentration (IC(50)) value increased significantly in the presence of a soluble UQ analog, p-aminobenzoic acid (pABA), or 4-HB. These results indicate the potential of AV combined with 4-NB as a novel therapy for malaria and other diseases caused by AV-sensitive pathogens. |
| تدمد: | 1098-6596 0066-4804 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1be3ad2bf42c03fd69cd8aa66e00d376 https://doi.org/10.1128/aac.01516-20 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....1be3ad2bf42c03fd69cd8aa66e00d376 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10986596 00664804 |
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