Davison_2022_iScience_25_104996

Malaria remains a global health issue requiring the identification of novel therapeuticstargets to combat drug resistance. Metabolic serine hydrolases are druggable enzymes playing essential roles in lipid metabolism. However, very few have been investigated in malaria-causing parasites. Here, we usedsfluorophosphonate broad-spectrum activity-based probes and quantitative chemical proteomics to annotate and profile the activity of more than half of predicted serine hydrolases in P. falciparum across the erythrocytic cycle.sUsing conditional genetics, we demonstrate that the activities of foursserine hydrolases, previously annotated as essential (or important) insgeneticsscreens, are actually dispensable for parasite replication. Of importance,swe also identified eight human serine hydrolases that are specificallysactivated at different developmental stages. Chemical inhibition of two of them blocks parasite replication. This strongly suggests that parasitessco-opt the activity of host enzymes and that this opens a new drug development strategy against which the parasites are less likely to develop resistance.