The antimalarial natural product salinipostin A identifies essential α/β serine hydrolases involved in lipid metabolism in P. falciparum parasites
2019
Salinipostin A (Sal A) is a potent antimalarial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain /{beta}
serine hydrolasedomains, and several are essential for parasite growth. One of the essential targets displays high homology to human
monoacylglycerol lipase(MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug
Orlistat, which disrupts lipid metabolism and produces disorganized and stalled schizonts similar to Sal A. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a protein linked to drug resistance in
Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the
non-essentialityof human homologs makes the
serine hydrolasesidentified here promising antimalarial targets.
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