Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention.

  • Journal Article

Journal:
Cell chemical biology
Published:
July 28, 2021
PMID:
34348113
Authors:
Robert L Summers RL, Charisse Flerida A Pasaje CFA, Joao P Pisco JP, Josefine Striepen J, Madeline R Luth MR, Krittikorn Kumpornsin K, Emma F Carpenter EF, Justin T Munro JT, De Lin , Andrew Plater A, Avinash S Punekar AS, Andrew M Shepherd AM, Sharon M Shepherd SM, Manu Vanaerschot M, James M Murithi JM, Kelly Rubiano K, Aslı Akidil A, Sabine Ottilie S, Nimisha Mittal N, A Hazel Dilmore AH, Madalyn Won M, Rebecca E K Mandt REK, Kerry McGowen K, Edward Owen E, Chris Walpole C, Manuel Llinás M, Marcus C S Lee MCS, Elizabeth A Winzeler EA, David A Fidock DA, Ian H Gilbert IH, Dyann F Wirth DF, Jacquin C Niles JC, Beatriz Baragaña B, Amanda K Lukens AK
Abstract:

We identify the Plasmodium falciparum acetyl-coenzyme A synthetase (PfAcAS) as a druggable target, using genetic and chemical validation. In vitro evolution of resistance with two antiplasmodial drug-like compounds (MMV019721 and MMV084978) selects for mutations in PfAcAS. Metabolic profiling of compound-treated parasites reveals changes in acetyl-CoA levels for both compounds. Genome editing confirms that mutations in PfAcAS are sufficient to confer resistance. Knockdown studies demonstrate that PfAcAS is essential for asexual growth, and partial knockdown induces hypersensitivity to both compounds. In vitro biochemical assays using recombinantly expressed PfAcAS validates that MMV019721 and MMV084978 directly inhibit the enzyme by preventing CoA and acetate binding, respectively. Immunolocalization studies reveal that PfAcAS is primarily localized to the nucleus. Functional studies demonstrate inhibition of histone acetylation in compound-treated wild-type, but not in resistant parasites. Our findings identify and validate PfAcAS as an essential, druggable target involved in the epigenetic regulation of gene expression.