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A Staphylococcus aureus Virulence Inhibitor Identified by SaeRS Refactoring and Screening in Bacillus subtilis

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: A Staphylococcus aureus Virulence Inhibitor Identified by SaeRS Refactoring and Screening in Bacillus subtilis
Συγγραφείς: Ekness, Felix, Wold, Eric A, Leasure, Catherine S, Musteata, Elena, Monteith, Andrew J, Laut, Clare
Πηγή: MaineHealth Maine Medical Center
Στοιχεία εκδότη: MaineHealth Knowledge Connection
Έτος έκδοσης: 2025
Συλλογή: MaineHealth Knowledge Connection
Θεματικοί όροι: Bacillus subtilis, Staphylococcus aureus, bacterial two-component system, inhibitor screen, sensor histidine kinase, virulence, Bacillus subtilis (genetics, metabolism, drug effects), Bacterial Proteins (genetics, antagonists & inhibitors), Staphylococcus aureus (drug effects, pathogenicity, genetics, metabolism), Virulence (drug effects), Anti-Bacterial Agents (pharmacology), Signal Transduction (drug effects), Histidine Kinase (metabolism, Gene Expression Regulation, Bacterial (drug effects), Phosphorylation (drug effects), Small Molecule Libraries (pharmacology), Protein Kinases, Transcription Factors
Περιγραφή: Bacteria utilize two-component system (TCS) signal transduction pathways to sense environmental and physiological stimuli and mount appropriate responses. In opportunistic pathogens such as Staphylococcus aureus, TCSs activate virulence programs in response to host defense systems. Due to their critical role in pathogenesis, TCSs are important targets for antivirulence drug discovery campaigns. However, challenges associated with screening TCSs in pathogens and in vitro have limited the output of such efforts to a small number of characterized drug candidates. Here, we functionally express the S. aureus virulence-regulating TCS SaeRS from synthetic gene regulatory elements in the model bacterium Bacillus subtilis to reliably screen this system against a small molecule library under simple culturing conditions. Our approach reveals the compound NSC97920 as a strong inhibitor of SaeRS signaling. We combine in situ, in vivo, in silico, and in vitro characterization to demonstrate that NSC97920 suppresses the critical step of autophosphorylation in the SaeS histidine kinase, resulting in strong antivirulence activity. Our work shows that heterologous expression and screening of TCSs in model bacteria could accelerate the development of therapeutics against antibiotic-resistant pathogens.
Τύπος εγγράφου: text
Γλώσσα: unknown
Relation: https://knowledgeconnection.mainehealth.org/mmc/3992
Διαθεσιμότητα: https://knowledgeconnection.mainehealth.org/mmc/3992
Αριθμός Καταχώρησης: edsbas.3264F6BA
Βάση Δεδομένων: BASE
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  – Url: https://knowledgeconnection.mainehealth.org/mmc/3992#
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PubType: Academic Journal
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Items – Name: Title
  Label: Title
  Group: Ti
  Data: A Staphylococcus aureus Virulence Inhibitor Identified by SaeRS Refactoring and Screening in Bacillus subtilis
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  Data: <searchLink fieldCode="AR" term="%22Ekness%2C+Felix%22">Ekness, Felix</searchLink><br /><searchLink fieldCode="AR" term="%22Wold%2C+Eric+A%22">Wold, Eric A</searchLink><br /><searchLink fieldCode="AR" term="%22Leasure%2C+Catherine+S%22">Leasure, Catherine S</searchLink><br /><searchLink fieldCode="AR" term="%22Musteata%2C+Elena%22">Musteata, Elena</searchLink><br /><searchLink fieldCode="AR" term="%22Monteith%2C+Andrew+J%22">Monteith, Andrew J</searchLink><br /><searchLink fieldCode="AR" term="%22Laut%2C+Clare%22">Laut, Clare</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: MaineHealth Maine Medical Center
– Name: Publisher
  Label: Publisher Information
  Group: PubInfo
  Data: MaineHealth Knowledge Connection
– Name: DatePubCY
  Label: Publication Year
  Group: Date
  Data: 2025
– Name: Subset
  Label: Collection
  Group: HoldingsInfo
  Data: MaineHealth Knowledge Connection
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Bacillus+subtilis%22">Bacillus subtilis</searchLink><br /><searchLink fieldCode="DE" term="%22Staphylococcus+aureus%22">Staphylococcus aureus</searchLink><br /><searchLink fieldCode="DE" term="%22bacterial+two-component+system%22">bacterial two-component system</searchLink><br /><searchLink fieldCode="DE" term="%22inhibitor+screen%22">inhibitor screen</searchLink><br /><searchLink fieldCode="DE" term="%22sensor+histidine+kinase%22">sensor histidine kinase</searchLink><br /><searchLink fieldCode="DE" term="%22virulence%22">virulence</searchLink><br /><searchLink fieldCode="DE" term="%22Bacillus+subtilis+%28genetics%22">Bacillus subtilis (genetics</searchLink><br /><searchLink fieldCode="DE" term="%22metabolism%22">metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22drug+effects%29%22">drug effects)</searchLink><br /><searchLink fieldCode="DE" term="%22Bacterial+Proteins+%28genetics%22">Bacterial Proteins (genetics</searchLink><br /><searchLink fieldCode="DE" term="%22antagonists+%26+inhibitors%29%22">antagonists & inhibitors)</searchLink><br /><searchLink fieldCode="DE" term="%22Staphylococcus+aureus+%28drug+effects%22">Staphylococcus aureus (drug effects</searchLink><br /><searchLink fieldCode="DE" term="%22pathogenicity%22">pathogenicity</searchLink><br /><searchLink fieldCode="DE" term="%22genetics%22">genetics</searchLink><br /><searchLink fieldCode="DE" term="%22metabolism%29%22">metabolism)</searchLink><br /><searchLink fieldCode="DE" term="%22Virulence+%28drug+effects%29%22">Virulence (drug effects)</searchLink><br /><searchLink fieldCode="DE" term="%22Anti-Bacterial+Agents+%28pharmacology%29%22">Anti-Bacterial Agents (pharmacology)</searchLink><br /><searchLink fieldCode="DE" term="%22Signal+Transduction+%28drug+effects%29%22">Signal Transduction (drug effects)</searchLink><br /><searchLink fieldCode="DE" term="%22Histidine+Kinase+%28metabolism%22">Histidine Kinase (metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Gene+Expression+Regulation%22">Gene Expression Regulation</searchLink><br /><searchLink fieldCode="DE" term="%22Bacterial+%28drug+effects%29%22">Bacterial (drug effects)</searchLink><br /><searchLink fieldCode="DE" term="%22Phosphorylation+%28drug+effects%29%22">Phosphorylation (drug effects)</searchLink><br /><searchLink fieldCode="DE" term="%22Small+Molecule+Libraries+%28pharmacology%29%22">Small Molecule Libraries (pharmacology)</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+Kinases%22">Protein Kinases</searchLink><br /><searchLink fieldCode="DE" term="%22Transcription+Factors%22">Transcription Factors</searchLink>
– Name: Abstract
  Label: Description
  Group: Ab
  Data: Bacteria utilize two-component system (TCS) signal transduction pathways to sense environmental and physiological stimuli and mount appropriate responses. In opportunistic pathogens such as Staphylococcus aureus, TCSs activate virulence programs in response to host defense systems. Due to their critical role in pathogenesis, TCSs are important targets for antivirulence drug discovery campaigns. However, challenges associated with screening TCSs in pathogens and in vitro have limited the output of such efforts to a small number of characterized drug candidates. Here, we functionally express the S. aureus virulence-regulating TCS SaeRS from synthetic gene regulatory elements in the model bacterium Bacillus subtilis to reliably screen this system against a small molecule library under simple culturing conditions. Our approach reveals the compound NSC97920 as a strong inhibitor of SaeRS signaling. We combine in situ, in vivo, in silico, and in vitro characterization to demonstrate that NSC97920 suppresses the critical step of autophosphorylation in the SaeS histidine kinase, resulting in strong antivirulence activity. Our work shows that heterologous expression and screening of TCSs in model bacteria could accelerate the development of therapeutics against antibiotic-resistant pathogens.
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  Data: https://knowledgeconnection.mainehealth.org/mmc/3992
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  Data: https://knowledgeconnection.mainehealth.org/mmc/3992
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  Data: edsbas.3264F6BA
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RecordInfo BibRecord:
  BibEntity:
    Languages:
      – Text: unknown
    Subjects:
      – SubjectFull: Bacillus subtilis
        Type: general
      – SubjectFull: Staphylococcus aureus
        Type: general
      – SubjectFull: bacterial two-component system
        Type: general
      – SubjectFull: inhibitor screen
        Type: general
      – SubjectFull: sensor histidine kinase
        Type: general
      – SubjectFull: virulence
        Type: general
      – SubjectFull: Bacillus subtilis (genetics
        Type: general
      – SubjectFull: metabolism
        Type: general
      – SubjectFull: drug effects)
        Type: general
      – SubjectFull: Bacterial Proteins (genetics
        Type: general
      – SubjectFull: antagonists & inhibitors)
        Type: general
      – SubjectFull: Staphylococcus aureus (drug effects
        Type: general
      – SubjectFull: pathogenicity
        Type: general
      – SubjectFull: genetics
        Type: general
      – SubjectFull: metabolism)
        Type: general
      – SubjectFull: Virulence (drug effects)
        Type: general
      – SubjectFull: Anti-Bacterial Agents (pharmacology)
        Type: general
      – SubjectFull: Signal Transduction (drug effects)
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      – SubjectFull: Histidine Kinase (metabolism
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      – SubjectFull: Gene Expression Regulation
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      – SubjectFull: Bacterial (drug effects)
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      – SubjectFull: Phosphorylation (drug effects)
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      – SubjectFull: Small Molecule Libraries (pharmacology)
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      – SubjectFull: Protein Kinases
        Type: general
      – SubjectFull: Transcription Factors
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    Titles:
      – TitleFull: A Staphylococcus aureus Virulence Inhibitor Identified by SaeRS Refactoring and Screening in Bacillus subtilis
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            NameFull: Ekness, Felix
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            NameFull: Wold, Eric A
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              Y: 2025
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            – TitleFull: MaineHealth Maine Medical Center
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