Discovery and mechanism of a highly selective, antifungal acetyl-CoA synthetase inhibitor
Acetyl-CoA synthetases (Acs) have emerged as drug targets for the treatment of cancer, metabolic diseases as well as fungal and parasitic infections. Although a variety of small molecule Acs inhibitors have been discovered, the systematic optimization of these molecules has been slowed by a lack of structural information regarding their mechanism of inhibition. Through a chemical genetic-based, synthetic lethal screen of the human fungal pathogen Cryptococcus neoformans, we identified an isoxazole-based Acs inhibitor with antifungal activity and high selectivity for the C. neoformans Acs1 relative to human ACSS2 as well as to other fungal Acs enzymes. Xray crystallography of the isoxazole-CnAcs1 complex revealed that the isoxazole occupies both the acetyl- and CoA-binding sites of CnAcs1. Biochemically, the isoxazoles display uncompetitive inhibition kinetics that are similar to antimalarial Acs inhibitors also proposed to target the CoA binding site. Consequently, these data provide structural and mechanistic insights into the remarkable selectivity of CoA pocket-targeting Acs inhibitors. As such, targeting fungal and parasitic Acs enzymes for the development of novel anti-infectives can be achieved with high selectivity and, thereby, low host toxicity.
Authors
- Scott Lovell (ORCID: https://orcid.org/0000-0002-3215-4472)
- Timothy J. Hagen (ORCID: https://orcid.org/0000-0003-1929-9121)
- Andrew J. Jezewski (ORCID: https://orcid.org/0000-0002-2004-1278)
- Bart L. Staker (ORCID: https://orcid.org/0000-0001-9570-5086)
- Juan Camilo Arjona Ferreira (ORCID: https://orcid.org/0000-0002-4514-4046)
- K.P. Battaile (ORCID: https://orcid.org/0000-0003-0833-3259)
- Katy M. Alden (ORCID: https://orcid.org/0000-0001-5339-1509)
- Jonah Propp
- Damian J. Krysan (ORCID: https://orcid.org/0000-0001-6330-3365)
- Drashti G. Daraji (ORCID: https://orcid.org/0000-0001-6697-4834)
- Noelle Sevilir Williams (ORCID: https://orcid.org/0000-0003-1894-5742)
- Lijun Liu (ORCID: https://orcid.org/0000-0002-6974-4417)
- Charles L. Lail
- Andrew Fuller
- Michael E. Heene
Institutions
- Northern Illinois University (US)
- University of Iowa (US)
- Center for Infectious Disease Research (US)
- Infectious Disease Research Institute (US)
- University of Kansas (US)
- New York Structural Biology Center (US)
- Southwestern Medical Center (US)
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-14
- DOI
- https://doi.org/10.1038/s41467-025-64183-7
- Citations
- 1
- Primary Topic
- Microbial Natural Products and Biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 1.39
Funders
- National Science Foundation
- U.S. Department of Energy
- National Institutes of Health
- Office of Science
- National Institute of Allergy and Infectious Diseases
- Division of Chemistry
- Brookhaven National Laboratory