4-nitrobenzoate inhibits 4-hydroxybenzoate polyprenyltransferase in malaria parasites and enhances atovaquone efficacy.

ABSTRACT: Ubiquinone (UQ) is essential for the electron transport chain in Plasmodium falciparum, the causative agent of severe malaria. Its biosynthesis begins with the condensation of 4-hydroxybenzoate (4-HB) and an isoprenoid chain, catalyzed by 4-HB polyprenyltransferase (4-HPT; COQ2 gene). Atovaquone (AV) inhibits the mitochondrial bc1 complex by competing with ubiquinol (UQH₂), but resistance to the synergic combination AV/proguanil therapy has emerged. Here, we show that 4-nitrobenzoate (4-NB) inhibits Pf4-HPT, enhances AV efficacy and selectivity, while preserving proguanil synergy. In Saccharomyces cerevisiae expressing PfCOQ2, 4-NB inhibited UQ biosynthesis. In vivo, 4-NB improved AV efficacy in Plasmodium berghei-infected mice. Structure-activity studies with 4-HB analogs further defined chemical features for potentiation. These findings support PfCOQ2 as a target to boost AV-based antimalarial therapy. Impact statement This study identifies a molecular rationale for enhancing atovaquone efficacy through targeted inhibition of ubiquinone biosynthesis. By validating PfCOQ2 as a druggable target and demonstrating in vivo potentiation, our findings offer strategic advance toward rational antimalarial combination therapies, moving beyond empirical approaches and addressing current resistance.

SUBMITTER: Verdaguer IB 

PROVIDER: S-EPMC12834005 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature