Exploring ubiquinone biosynthesis inhibition as a strategy for improving atovaquone efficacy in malaria.

Abstract:

:Atovaquone (AV) acts on the malaria parasite by competing with ubiquinol (UQH2) for its union to the mitochondrial bc1 complex, preventing the ubiquinone-8,9 (UQ) 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 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 IC50 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.

authors

Verdaguer IB,Crispim M,Zafra CA,Sussmann RAC,Buriticá NL,Melo HR,Azevedo MF,Almeida FG,Kimura EA,Katzin AM

doi

10.1128/AAC.01516-20

subject

Has Abstract

pub_date

2021-01-25 00:00:00

eissn

0066-4804

issn

1098-6596

pii

AAC.01516-20

pub_type

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