Identification of a s. Aureus virulence factor by activity-based protein profiling (abpp)

ABSTRACT Serine hydrolases play diverse roles in regulating host–pathogen interactions in a number of organisms, yet few have been characterized in the human pathogen _Staphylococcus

aureus_. Here we describe a chemical proteomic screen that identified ten previously uncharacterized _S. aureus_ serine hydrolases that mostly lack human homologs. We termed these enzymes

fluorophosphonate-binding hydrolases (FphA–J). One hydrolase, FphB, can process short fatty acid esters, exhibits increased activity in response to host cell factors, is located

predominantly on the bacterial cell surface in a subset of cells, and is concentrated in the division septum. Genetic disruption of _fphB_ confirmed that the enzyme is dispensable for

bacterial growth in culture but crucial for establishing infection in distinct sites in vivo. A selective small molecule inhibitor of FphB effectively reduced infectivity in vivo, suggesting

that it may be a viable therapeutic target for the treatment or management of _Staphylococcus_ infections. Access through your institution Buy or subscribe This is a preview of subscription

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* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS IDENTIFICATION OF COVALENT INHIBITORS OF _STAPHYLOCOCCUS AUREUS_

SERINE HYDROLASES IMPORTANT FOR VIRULENCE AND BIOFILM FORMATION Article Open access 30 May 2025 MURG AS A POTENTIAL TARGET OF QUERCETIN IN _STAPHYLOCOCCUS AUREUS_ SUPPORTED BY EVIDENCE FROM

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PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank A. Horswill (University of Iowa) for sharing the GFP plasmid pCM29. We thank N. Amara and J. Yim for help with NMR

analyses and S. Chen for LC-MS analysis of JCP678, and L. Popov, O. Zurek, J. Romaniuk and L. Cegelski for discussions. We also thank E. Yeh for access to the BD Accuri flow cytometer.

C.S.L. was supported through a postdoctoral research fellowship by the German Research Foundation (DFG). This work was further supported through NIH grants 1R01GM111703 and R01EB026332 to

M.B., 1R01GM117004 and 1R01GM118431-01A1 to E.W., 1R01AI101171 and 1R01AI069233 to E.P.S., and R21AI117255 to M.R.A. AUTHOR INFORMATION Author notes * These authors contributed equally:

Christian S. Lentz, Jessica R. Sheldon. AUTHORS AND AFFILIATIONS * Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA Christian S. Lentz, Megan Garland & 

Matthew Bogyo * Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA Jessica R. Sheldon & Eric P. Skaar * Department of

Chemistry, Boston College, Chestnut Hill, MA, USA Lisa A. Crawford & Eranthie Weerapana * Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA Rachel

Cooper & Manuel R. Amieva * Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA Manuel R. Amieva & Matthew Bogyo Authors * Christian

S. Lentz View author publications You can also search for this author inPubMed Google Scholar * Jessica R. Sheldon View author publications You can also search for this author inPubMed 

Google Scholar * Lisa A. Crawford View author publications You can also search for this author inPubMed Google Scholar * Rachel Cooper View author publications You can also search for this

author inPubMed Google Scholar * Megan Garland View author publications You can also search for this author inPubMed Google Scholar * Manuel R. Amieva View author publications You can also

search for this author inPubMed Google Scholar * Eranthie Weerapana View author publications You can also search for this author inPubMed Google Scholar * Eric P. Skaar View author

publications You can also search for this author inPubMed Google Scholar * Matthew Bogyo View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS

C.S.L. and M.B. conceived the project. C.S.L designed and performed the in vitro experiments, synthesized compounds and analyzed data. J.R.S. designed and performed the in vivo infection

experiments and the genetic manipulation of _S. aureus_, and analyzed data. L.A.C. and E.W. performed LC-MS/MS analysis. R.C. contributed to the comparative bacterial labeling experiments.

M.G. synthesized compounds. M.R.A. contributed to the experimental design and analyzed data. E.P.S. designed and analyzed in vivo infection experiments. M.B. supervised the project, designed

experiments and analyzed data. C.S.L. and M.B. wrote the manuscript, and all authors reviewed, discussed and edited the manuscript. CORRESPONDING AUTHOR Correspondence to Matthew Bogyo.

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional

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REPORTING SUMMARY SUPPLEMENTARY DATASET 1 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Lentz, C.S., Sheldon, J.R., Crawford, L.A. _et al._

Identification of a _S. aureus_ virulence factor by activity-based protein profiling (ABPP). _Nat Chem Biol_ 14, 609–617 (2018). https://doi.org/10.1038/s41589-018-0060-1 Download citation *

Received: 18 October 2017 * Accepted: 27 March 2018 * Published: 16 May 2018 * Issue Date: June 2018 * DOI: https://doi.org/10.1038/s41589-018-0060-1 SHARE THIS ARTICLE Anyone you share the

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