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dc.contributor.authorFellner, Matthias
dc.contributor.authorWalsh, Annabel
dc.contributor.authorAhator, Stephen Dela
dc.contributor.authorAftab, Nadia
dc.contributor.authorSutherland, Ben
dc.contributor.authorTan, Eng W
dc.contributor.authorBakker, Alexander T
dc.contributor.authorMartin, Nathaniel I
dc.contributor.authorvan der Stelt, Mario
dc.contributor.authorLentz, Christian Stephan
dc.date.accessioned2024-02-01T10:19:37Z
dc.date.available2024-02-01T10:19:37Z
dc.date.issued2023-10-12
dc.description.abstractThe development of new treatment options for bacterial infections requires access to new targets for antibiotics and antivirulence strategies. Chemoproteomic approaches are powerful tools for profiling and identifying novel druggable target candidates, but their functions often remain uncharacterized. Previously, we used activity-based protein profiling in the opportunistic pathogen Staphylococcus aureus to identify active serine hydrolases termed fluorophosphonate-binding hydrolases (Fph). Here, we provide the first characterization of S. aureus FphH, a conserved, putative carboxylesterase (referred to as yvaK in Bacillus subtilis) at the molecular and cellular level. First, phenotypic characterization of fphH-deficient transposon mutants revealed phenotypes during growth under nutrient deprivation, biofilm formation, and intracellular survival. Biochemical and structural investigations revealed that FphH acts as an esterase and lipase based on a fold well suited to act on a small to long hydrophobic unbranched lipid group within its substrate and can be inhibited by active site-targeting oxadiazoles. Prompted by a previous observation that fphH expression was upregulated in response to fusidic acid, we found that FphH can deacetylate this ribosome-targeting antibiotic, but the lack of FphH function did not infer major changes in antibiotic susceptibility. In conclusion, our results indicate a functional role of this hydrolase in S. aureus stress responses, and hypothetical functions connecting FphH with components of the ribosome rescue system that are conserved in the same gene cluster across Bacillales are discussed. Our atomic characterization of FphH will facilitate the development of specific FphH inhibitors and probes to elucidate its physiological role and validity as a drug target.en_US
dc.identifier.citationFellner, Walsh, Ahator, Aftab, Sutherland, Tan, Bakker, Martin, van der Stelt, Lentz. Biochemical and Cellular Characterization of the Function of Fluorophosphonate-Binding Hydrolase H (FphH) in Staphylococcus aureus Support a Role in Bacterial Stress Response. ACS Infectious Diseases. 2023;9(11):2119-2132en_US
dc.identifier.cristinIDFRIDAID 2186251
dc.identifier.doi10.1021/acsinfecdis.3c00246
dc.identifier.issn2373-8227
dc.identifier.urihttps://hdl.handle.net/10037/32815
dc.language.isoengen_US
dc.publisherACS Publicationsen_US
dc.relation.journalACS Infectious Diseases
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2023 The Author(s)en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0en_US
dc.rightsAttribution 4.0 International (CC BY 4.0)en_US
dc.titleBiochemical and Cellular Characterization of the Function of Fluorophosphonate-Binding Hydrolase H (FphH) in Staphylococcus aureus Support a Role in Bacterial Stress Responseen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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Attribution 4.0 International (CC BY 4.0)
Med mindre det står noe annet, er denne innførselens lisens beskrevet som Attribution 4.0 International (CC BY 4.0)