Identification of covalent inhibitors of Staphylococcus aureus serine hydrolases important for virulence and biofilm formation

Tulsi Upadhyay, Emily C. Woods, Stephen Ahator, Kjersti Julin, Franco F. Faucher, Md Jalal Uddin, Marijn J. Hollander, Nichole J. Pedowitz, Daniel Abegg, Isabella Hammond, Ifeanyichukwu E. Eke, Sijie Wang, Shiyu Chen, John M. Bennett, Jeyun Jo, Christian S. Lentz, Alexander Adibekian, Matthias Fellner and Matthew Bogyo ()
Additional contact information
Tulsi Upadhyay: Stanford University School of Medicine
Emily C. Woods: Stanford University School of Medicine
Stephen Ahator: UiT─The Arctic University of Norway
Kjersti Julin: UiT─The Arctic University of Norway
Franco F. Faucher: Stanford University
Md Jalal Uddin: UiT─The Arctic University of Norway
Marijn J. Hollander: Stanford University School of Medicine
Nichole J. Pedowitz: Stanford University School of Medicine
Daniel Abegg: University of Illinois Chicago
Isabella Hammond: Stanford University School of Medicine
Ifeanyichukwu E. Eke: Stanford University School of Medicine
Sijie Wang: Stanford University School of Medicine
Shiyu Chen: Stanford University School of Medicine
John M. Bennett: Stanford University
Jeyun Jo: Stanford University School of Medicine
Christian S. Lentz: UiT─The Arctic University of Norway
Alexander Adibekian: University of Illinois Chicago
Matthias Fellner: University of Otago
Matthew Bogyo: Stanford University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Staphylococcus aureus is a leading cause of bacteria-associated mortality worldwide. New tools are needed to both image and treat this pathogen. We previously identified a group of S. aureus serine hydrolases (Fphs), which regulate aspects of virulence and lipid metabolism. However, due to high structural and functional similarities, it remains challenging to distinguish the specific roles of members of this family. Here, we apply a high-throughput screening approach using a library of covalent electrophiles to identify inhibitors for FphB, FphE, and FphH. We identify selective covalent inhibitors for each target without the need for extensive medicinal chemistry optimization. Structural and biochemical analysis identify novel binding modes for several of the inhibitors. Functional studies using the inhibitors suggest that all three hydrolases likely play distinct functional roles in biofilm formation and virulence. This approach has the potential to be applied to target hydrolases in other diverse pathogens or higher eukaryotes.

Date: 2025
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-60367-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60367-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-60367-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().