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Identification of Staphylococcus aureus Cellular Pathways Affected by the Stilbenoid Lead Drug SK-03-92 Using a

William R Schwan1,2, Rebecca Polanowski3,4, Paul M Dunman5

  • 1Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. wschwan@uwlax.edu.

Antibiotics (Basel, Switzerland)
|September 12, 2017
PubMed
Summary
This summary is machine-generated.

A new compound, SK-03-92, shows bactericidal effects against methicillin-resistant Staphylococcus aureus (MRSA). Transcriptional profiling revealed that SK-03-92 affects genes involved in sortase A production and a two-component system, offering insights into its mechanism of action.

Keywords:
Staphylococcus aureusbiofilmdrug mechanism of actiongene regulationmicroarraysortasestilbene

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Area of Science:

  • Microbiology
  • Molecular Biology
  • Pharmacology

Background:

  • Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant public health threat due to its resistance to conventional antibiotics.
  • The precise mechanism of action for novel bactericidal compounds like SK-03-92 against MRSA remains largely uncharacterized.
  • Understanding the molecular pathways affected by new antimicrobial agents is crucial for developing effective treatments.

Purpose of the Study:

  • To elucidate the mechanism of action of the novel stilbene compound SK-03-92 against MRSA.
  • To identify cellular pathways and genes regulated by SK-03-92 treatment in S. aureus.
  • To investigate the potential role of a specific two-component system in regulating gene expression in response to SK-03-92.

Main Methods:

  • Transcriptional profiling (RNA sequencing) was employed to compare gene expression in S. aureus treated with SK-03-92 versus untreated controls.
  • Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the expression levels of selected upregulated and downregulated genes.
  • Gene expression analysis of specific mutants (MW2284 and MW2285) was performed to assess their impact on the regulation of other genes, such as srtA.

Main Results:

  • SK-03-92 treatment resulted in the upregulation of 14 genes and downregulation of 38 genes in S. aureus.
  • Upregulated genes were associated with sortase A production, protein metabolism, and transcriptional regulation.
  • Downregulated genes included those encoding transporters, purine biosynthesis proteins, and a putative two-component system (SACOL2360/MW2284 and SACOL2361/MW2285).
  • qRT-PCR confirmed the differential expression of srtA, tdk, purine biosynthesis genes, and the MW2284/MW2285 system.
  • Mutants of the putative two-component system (MW2284/MW2285) showed altered regulation of srtA, suggesting its involvement in controlling srtA expression.

Conclusions:

  • SK-03-92 modulates multiple cellular pathways in S. aureus, including those related to sortase A and purine biosynthesis.
  • A putative two-component system (MW2284/MW2285) appears to play a regulatory role in response to SK-03-92, potentially influencing srtA expression.
  • These findings provide valuable insights into the mechanism of action of SK-03-92 and suggest its potential impact on biofilm formation and drug persisters.