A Malaria Transmission-Blocking (+)-Usnic Acid Derivative Prevents Plasmodium Zygote-to-Ookinete Maturation in the Mosquito Midgut

• DOI: 10.1021/acschembio.6b00902
• Publication Date: 2016-11-07T21:42:57Z
• Authors: Rebecca Pastrana-...; Derrick K. Mathias; Michael Delves; Krithika Rajaram; Jonas G. King; Rebecca Yee; Beatrice Trucchi; Luisella Verotta; Rhoel R. Dinglasan
• Keywords: Plasmodium berghei; Plasmodium (life cycle)

The evolution of drug resistance is a recurrent problem that has plagued efforts to treat and control malaria. Recent emergence artemisinin in Southeast Asia underscores the need develop novel antimalarials identify new targetable pathways Plasmodium parasites. Transmission-blocking approaches, which typically target gametocytes host bloodstream or parasite stages mosquito gut, are recognized collectively as strategy when used combination with erythrocytic will not only cure malaria but also prevent subsequent transmission. We tested four derivatives (+)-usnic acid, metabolite isolated from lichens, for transmission-blocking activity against falciparum using standard membrane feeding assay. For two derivatives, BT37 BT122, we observed consistent dose-response relationship between concentration blood meal oocyst intensity midgut. To explore their mechanism action, murine model berghei found both ookinete maturation. Using fluorescence microscopy, demonstrated presence each compound zygote vitality was severely affected, those did survive failed elongate mature into ookinetes. phenotypes were similar described mutants specific kinases (NEK2/NEK4) inner complex 1 (IMC1) proteins, all vital zygote-to-ookinete transition. discuss implications our findings high-throughput screening approach identifying next generation, based on scaffolds these acid derivatives.