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Cell Chem Biol DOI:10.1016/j.chembiol.2021.07.010

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

Publication TypeJournal Article
Year of Publication2021
AuthorsSummers, RL, Pasaje, CFlerida A, Pisco, JP, Striepen, J, Luth, MR, Kumpornsin, K, Carpenter, EF, Munro, JT, Lin, D, Plater, A, Punekar, AS, Shepherd, AM, Shepherd, SM, Vanaerschot, M, Murithi, JM, Rubiano, K, Akidil, A, Ottilie, S, Mittal, N, A Dilmore, H, Won, M, Mandt, REK, McGowen, K, Owen, E, Walpole, C, Llinás, M, Lee, MCS, Winzeler, EA, Fidock, DA, Gilbert, IH, Wirth, DF, Niles, JC, Baragaña, B, Lukens, AK
JournalCell Chem Biol
Date Published2021 Jul 28
ISSN2451-9448
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.

DOI10.1016/j.chembiol.2021.07.010
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/34348113?dopt=Abstract

Alternate JournalCell Chem Biol
PubMed ID34348113