Beyond the MEP pathway: a new kinase required for prenol utilization by malaria parasites

Falciparum malaria is a potentially fatal disease caused by the Plasmodium falciparum parasite. Antimalarials such as fosmidomycin and clindamycin target a critical pathway in the parasite that is crucial for the production of certain substances essential for the parasite’s survival, particularly phosphorylated isoprenoids. However, the limited effectiveness of these medicines in clinical trials for the treatment of malaria highlights the need for further related studies. Previous in vitro experiments have demonstrated that the parasite can utilize non-phosphorylated isoprenoids, namely farnesol and geranylgeraniol, if they are present in the external environment. Thus, these substances act as antidotes, making the parasite resistant to both fosmidomycin and clindamycin. This study reveals for the first time that geranylgeraniol occurs naturally in the human body. Furthermore, a new enzyme was identified, prenol kinase, that allows the parasite to use these unphosphorylated isoprenoids, converting them into their metabolically active phosphorylated counterparts. Parasites lacking the prenol kinase gene remain viable but become more susceptible to the effects of fosmidomycin, even in the presence of farnesol or geranylgeraniol. These findings suggest that elimination of non-phosphorylated isoprenoids by the parasite may supplement its isoprenoid needs when endogenous production is inhibited by drugs such as fosmidomycin or clindamycin.

Project details

Basic Science
Drug Resistance

Apr 2024 — Sep 2024

Brazil