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Modulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO

Yunfu Lu1,2,3, Feifei Chen1,2,4, Qingmin Zhao1,2,3

  • 1School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.

Nature Communications
|March 23, 2023
PubMed

Insights

Inhibiting TarO, crucial for wall teichoic acid (WTA) synthesis, reduces virulence factors like PSMs and SpA in community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). This occurs via VraRS activation, offering a potential anti-virulence therapeutic target.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Pathogenesis

Background:

  • Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a significant pathogen.
  • Phenol-soluble modulins (PSMs) and Staphylococcal protein A (SpA) are critical virulence factors in CA-MRSA.

Purpose of the Study:

  • To investigate the role of wall teichoic acid (WTA) biosynthesis in regulating CA-MRSA virulence gene expression.
  • To identify the molecular mechanisms linking WTA synthesis inhibition to virulence factor downregulation.

Main Methods:

  • Chemical inhibition of TarO, the initial enzyme in WTA biosynthesis.
  • Genetic approaches to study virulence gene regulation.
  • Analysis of the VraRS two-component system and its targets (agr, spa).
  • Investigation of penicillin-binding protein 2 (PBP2) and PBP2a involvement.
  • Assessment of lipid-linked peptidoglycan precursor accumulation.

Main Results:

  • TarO inhibition significantly decreases the expression of PSMs and SpA in CA-MRSA strain USA300 LAC.
  • This downregulation is mediated by the activation of the VraRS two-component system.
  • VraRS activation represses the accessory gene regulator (agr) locus and spa expression.
  • VraRS activation is partly dependent on the functional integrity of PBP2 (via PBP2a) but can also occur independently.
  • Accumulation of lipid-linked peptidoglycan precursors triggers VraRS activation.

Conclusions:

  • WTA biosynthesis is a key regulator of virulence gene expression in CA-MRSA.
  • TarO is a promising target for developing novel anti-virulence therapies against CA-MRSA.
  • The mecA gene, encoding PBP2a, adds a regulatory layer to signaling pathways in Staphylococcus aureus.

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