The heme A synthase Cox15, as a target of redox-active 3-benzylmenadiones with antiparasitic activity.

Fiche publication

Date publication

décembre 2025

Journal

Antimicrobial agents and chemotherapy

Auteurs

Membres identifiés du Cancéropôle Est :
Dr DAVIOUD-CHARVET Elisabeth

Tous les auteurs :
Merli ML, Serot C, Vallières C, Cricco JA, Iorga BI, Davioud-Charvet E, Meunier B

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/41369564

Résumé

Chagas disease, caused by , is a neglected parasitic infection. The very limited arsenal of anti-. treatments calls for the development of new drugs. Recently, a library of 3-benzylmenadione derivatives was synthesized, with cruzidione being the most efficient and specific compound against the parasite. To decipher its mode of action, we used the yeast as a model. Evidence pinpointed at the heme A synthase Cox15 as a primary target of cruzidione: (i) a mutation in Cox15 (i.e., S429F) renders the yeast cells highly sensitive to the drug, (ii) treatment with cruzidione led to the loss of cytochrome oxidase, an enzyme that relies on heme A as an essential cofactor, and (iii) replacement of the yeast Cox15 by enzyme resulted in a high sensitivity to cruzidione. We then investigated the effect of cruzidione in and observed a significant reduction in the heme contents, most likely involving the inhibition of the heme A synthase. This, in turn, led to a decrease in O consumption by the parasite. Finally, using the yeast model, we showed that, similar to what we previously found for the antimalarial benzylmenadione plasmodione, NADH-dehydrogenase plays a key role in cruzidione bioactivation. We proposed that the reduced benzoylmenadione metabolites, produced by the reaction with NADH-dehydrogenase, act as Cox15 inhibitors. This study, through the identification of the mode of action of cruzidione, highlighted Cox15 as a novel target for antiparasitic drugs.