The antimalarial natural product salinipostin A identifies essential α/β serine hydrolases involved in lipid metabolism in P. falciparum parasites

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 α/β serine hydrolase domains, and several ar...

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Published inbioRxiv
Main Authors Yoo, Euna, Schulze, Christopher J, Stokes, Barbara H, Ouma Onguka, Yeo, Tomas, Mok, Sachel, Gnadig, Nina F, Zhou, Yani, Kurita, Kenji, Foe, Ian T, Terrell, Stephanie M, Boucher, Michael J, Cieplak, Piotr, Linington, Roger G, Long, Jonathan Z, Uhlemann, Anne-Catrin, Weerapana, Eranthie, Fidock, David A, Bogyo, Matthew
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 01.11.2019
Subjects
Antimalarial agents
Drug resistance
Esters
Homology
Hydrolase
Lipase
Lipid metabolism
Lipids
Metabolism
Natural products
Parasite resistance
Parasites
Plasmodium falciparum
Schizonts
Serine
Serine hydrolase
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Summary: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 α/β serine hydrolase domains, 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-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets.
DOI:10.1101/827287