Journal article
Discovery and mechanism of a highly selective, antifungal acetyl-CoA synthetase inhibitor
Nature communications, Vol.16(1), 9118
10/14/2025
DOI: 10.1038/s41467-025-64183-7
PMCID: PMC12521546
PMID: 41087359
Abstract
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.
Details
- Title: Subtitle
- Discovery and mechanism of a highly selective, antifungal acetyl-CoA synthetase inhibitor
- Creators
- Andrew J. Jezewski - University of IowaKaty M. Alden - Department of Pediatrics, Carver College of Medicine, University of IowaJonah Propp - University of IowaDrashti G. Daraji - Northern Illinois UniversityCharles L. Lail - Northern Illinois UniversityMichael E. Heene - Northern Illinois UniversityAndrew J. Fuller - University of IowaJeffery C. Ferreira - Northern Illinois UniversityLijun Liu - University of KansasKevin P. Battaile - New York Structural Biology CenterNoelle S. Williams - Southwestern Medical CenterBart L. Staker - Center for Global Infectious Disease Research Seattle Children’s Research Institute, Seattle Structural Genomics Center for Infectious Disease (SSGCID)Scott Lovell - University of KansasTimothy J. Hagen - Northern Illinois UniversityDamian J. Krysan - Department of Pediatrics, Carver College of Medicine, University of Iowa, Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.16(1), 9118
- DOI
- 10.1038/s41467-025-64183-7
- PMID
- 41087359
- PMCID
- PMC12521546
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Nature Publishing Group UK; BERLIN
- Grant note
- This work was supported by NIH grants 5R01AI161973 (D.J.K.) and T32AI007511 (A.J.J. and J.P.) This project has been funded in whole or in part by Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health under Contract No. 75N93022C00036. This research used resources at the NYX beamline 19-ID, supported by the New York Structural Biology Center, at the National Synchrotron Light Source II, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory under Contract No. DE-SC0012704. The NYX detector instrumentation was supported by grant S10OD030394 through the Office of the Director of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The purchase of the NMR spectrometer used to obtain results included in this publication was supported by the National Science Foundation under the MRI award CHE-2117776 (T.J.H). The HRMS was supported by Northern Illinois University Molecular Analysis Core Facility (RRID:SCR 024586), which was established as a partnership with Shimadzu Scientific Instruments. Purchase of the Bruker Maxis Plus QTOF was made possible by the National Science Foundation under Grant No. 1726931.
- Language
- English
- Date published
- 10/14/2025
- Academic Unit
- Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9985014897002771
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