Staphylococcus aureus PerR Is a Hypersensitive Hydrogen Peroxide Sensor using Iron-mediated Histidine Oxidation

Area of Science:

• Microbiology
• Molecular Biology
• Biochemistry

Background:

• PerR proteins are key peroxide sensors in Gram-positive bacteria, regulating gene expression via metal cofactor binding.
• Bacillus subtilis PerR (PerRBS) uses Fe(2+) or Mn(2+) but only Fe(2+)-bound form senses H2O2.
• Staphylococcus aureus PerR (PerRSA) is crucial for H2O2 resistance and virulence, but its sensing mechanism was unclear.

Purpose of the Study:

• To elucidate the metal cofactor dependency and H2O2 sensing mechanism of Staphylococcus aureus PerR (PerRSA).
• To investigate the correlation between PerRSA activity, H2O2 resistance, and virulence in S. aureus.

Main Methods:

• Biochemical assays to determine PerRSA's interaction with Fe(2+) and Mn(2+) under varying H2O2 concentrations.
• Analysis of PerRSA's response to physiological levels of H2O2.
• Correlation studies linking PerRSA activity to bacterial virulence and H2O2 resistance.

Main Results:

• PerRSA utilizes both Fe(2+) and Mn(2+) as cofactors.
• The Fe(2+)-bound form of PerRSA senses H2O2 via iron-mediated histidine oxidation, similar to PerRBS.
• PerRSA exhibits hypersensitivity to low H2O2 levels, explaining its apparent Mn(2+)-specific activity under aerobic conditions.
• PerRSA activity positively correlates with virulence and negatively with H2O2 resistance.

Conclusions:

• Staphylococcus aureus PerRSA employs a dual metal cofactor system for H2O2 sensing, with iron-mediated oxidation being key.
• PerRSA's heightened sensitivity to H2O2 suggests a critical role in sensing endogenous peroxide levels during infection.
• PerRSA represents a potential therapeutic target for controlling S. aureus pathogenesis due to its link with virulence.