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

Robert L Summers; Charisse Flerida A Pasaje; Joao P Pisco; Josefine Striepen; Madeline R Luth; Krittikorn Kumpornsin; Emma F Carpenter; Justin T Munro; De Lin; Andrew Plater; Avinash S Punekar; Andrew M Shepherd; Sharon M Shepherd; Manu Vanaerschot; James M Murithi; Kelly Rubiano; Aslı Akidil; Sabine Ottilie; Nimisha Mittal; A Hazel Dilmore; Madalyn Won; Rebecca E K Mandt; Kerry McGowen; Edward Owen; Chris Walpole; Manuel Llinás; Marcus C S Lee; Elizabeth A Winzeler; David A Fidock; Ian H Gilbert; Dyann F Wirth; Jacquin C Niles; Beatriz Baragaña; Amanda K Lukens

doi:10.1016/j.chembiol.2021.07.010

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

Cell Chem Biol. 2022 Feb 17;29(2):191-201.e8. doi: 10.1016/j.chembiol.2021.07.010. Epub 2021 Aug 3.

Authors

Robert L Summers¹, Charisse Flerida A Pasaje², Joao P Pisco³, Josefine Striepen⁴, Madeline R Luth⁵, Krittikorn Kumpornsin⁶, Emma F Carpenter⁶, Justin T Munro⁷, De Lin³, Andrew Plater³, Avinash S Punekar³, Andrew M Shepherd³, Sharon M Shepherd³, Manu Vanaerschot⁴, James M Murithi⁴, Kelly Rubiano⁴, Aslı Akidil⁶, Sabine Ottilie⁵, Nimisha Mittal⁵, A Hazel Dilmore⁵, Madalyn Won⁸, Rebecca E K Mandt⁸, Kerry McGowen⁸, Edward Owen⁹, Chris Walpole¹⁰, Manuel Llinás¹¹, Marcus C S Lee⁶, Elizabeth A Winzeler⁵, David A Fidock¹², Ian H Gilbert³, Dyann F Wirth¹³, Jacquin C Niles¹⁴, Beatriz Baragaña¹⁵, Amanda K Lukens¹⁶

Affiliations

¹ Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Research School of Biology, Australian National University, Canberra, ACT 2601, Australia.
² Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
⁴ Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁵ Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
⁶ Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
⁷ Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA; Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16802, USA.
⁸ Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁹ Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16802, USA; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
¹⁰ Structural Genomics Consortium, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
¹¹ Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA; Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16802, USA; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
¹² Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
¹³ Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Infectious Disease and Microbiome Program, The Broad Institute, Cambridge, MA 02142, USA.
¹⁴ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Infectious Disease and Microbiome Program, The Broad Institute, Cambridge, MA 02142, USA.
¹⁵ Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK. Electronic address: b.baragana@dundee.ac.uk.
¹⁶ Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Infectious Disease and Microbiome Program, The Broad Institute, Cambridge, MA 02142, USA. Electronic address: alukens@broadinstitute.org.

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.

Keywords: Plasmodium falciparum; acetyl-CoA synthetase; antimalarial; drug development; drug target identification; histone acetylation; malaria; mechanism of action.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetate-CoA Ligase / antagonists & inhibitors*
Acetate-CoA Ligase / metabolism
Antimalarials / chemistry
Antimalarials / pharmacology*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Malaria / drug therapy*
Malaria / metabolism
Models, Molecular
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Plasmodium falciparum / enzymology

Substances

Antimalarials
Enzyme Inhibitors
Acetate-CoA Ligase

Abstract

Publication types

MeSH terms

Substances

Grants and funding