Fiche publication
Date publication
septembre 2024
Journal
ACS infectious diseases
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIOUD-CHARVET Elisabeth
Tous les auteurs :
Dupouy B, Donzel M, Roignant M, Charital S, Keumoe R, Yamaryo-Botté Y, Feckler A, Bundschuh M, Bordat Y, Rottmann M, Mäser P, Botté CY, Blandin SA, Besteiro S, Davioud-Charvet E
Lien Pubmed
Résumé
The apicoplast is an essential organelle for the viability of apicomplexan parasites or , which has been proposed as a suitable drug target for the development of new antiplasmodial drug-candidates. Plasmodione, an antimalarial redox-active lead drug is active at low nM concentrations on several blood stages of such as early rings and gametocytes. Nevertheless, its precise biological targets remain unknown. Here, we described the synthesis and the evaluation of new heteroaromatic analogues of plasmodione, active on asexual blood stages and tachyzoites. Using a bioimaging-based analysis, we followed the morphological alterations of tachyzoites and revealed a specific loss of the apicoplast upon drug treatment. Lipidomic and fluxomic analyses determined that drug treatment severely impacts apicoplast-hosted FASII activity in tachyzoites, further supporting that the apicoplast is a primary target of plasmodione analogues. To follow the drug localization, "clickable" analogues of plasmodione were designed as tools for fluorescence imaging through a Cu(I)-catalyzed azide-alkyne cycloaddition reaction. Short-time incubation of two probes with trophozoites and tachyzoites showed that the clicked products localize within, or in the vicinity of, the apicoplast of both parasites. In , the fluorescence signal was also associated with the mitochondrion, suggesting that bioactivation and activity of plasmodione and related analogues are potentially associated with these two organelles in malaria parasites.
Mots clés
CuAAC-based imaging, Plasmodium falciparum, Toxoplasma gondii, apicoplast, lipidomics, plasmodione
Référence
ACS Infect Dis. 2024 09 26;:
