MerA functions as a hypothiocyanous acid reductase and defense mechanism in Staphylococcus aureus

• Published in: Molecular microbiology Vol. 119; no. 4; pp. 456 - 470
• Main Authors: Shearer, Heather L., Loi, Vu V., Weiland, Paul, Bange, Gert, Altegoer, Florian, Hampton, Mark B., Antelmann, Haike, Dickerhof, Nina
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.04.2023
• Subjects: Defense mechanisms; Derepression; Disulfide reductase; Disulfides; Heme peroxidase; Humans; HypR; Inactivation; MRSA; Oxidants; Oxidative stress; Oxidizing agents; Oxidoreductases - metabolism; Penicillin; RclA; Reductases; Respiratory tract; Sensitizing; SPD_1415; Staphylococcus aureus; Staphylococcus aureus - enzymology; Staphylococcus aureus - metabolism; Structure-function relationships; RclA; SPD_1415; HypR; Heme peroxidase; MRSA
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/mmi.15035

The major pathogen Staphylococcus aureus has to cope with host‐derived oxidative stress to cause infections in humans. Here, we report that S. aureus tolerates high concentrations of hypothiocyanous acid (HOSCN), a key antimicrobial oxidant produced in the respiratory tract. We discovered that the flavoprotein disulfide reductase (FDR) MerA protects S. aureus from this oxidant by functioning as a HOSCN reductase, with its deletion sensitizing bacteria to HOSCN. Crystal structures of homodimeric MerA (2.4 Å) with a Cys43–Cys48 intramolecular disulfide, and reduced MerACys43S (1.6 Å) showed the FAD cofactor close to the active site, supporting that MerA functions as a group I FDR. MerA is controlled by the redox‐sensitive repressor HypR, which we show to be oxidized to intermolecular disulfides under HOSCN stress, resulting in its inactivation and derepression of merA transcription to promote HOSCN tolerance. Our study highlights the HOSCN tolerance of S. aureus and characterizes the structure and function of MerA as a major HOSCN defense mechanism. Crippling the capacity to respond to HOSCN may be a novel strategy for treating S. aureus infections. The Staphylococcus aureus repressor HypR senses and responds to the immune‐derived oxidant hypothiocyanous acid (HOSCN) via a thiol‐switch‐mechanism to control expression of merA. MerA functions as a HOSCN reductase, protecting S. aureus from the oxidant.