Abstract
Staphylococcus aureus is a major human pathogen, which encounters reactive oxygen, nitrogen, chlorine, electrophile and sulfur species (ROS, RNS, RCS, RES and RSS) by the host immune system, during cellular metabolism or antibiotics treatments. To defend against redox active species and antibiotics, S.aureus is equipped with redox sensing regulators that often use thiol switches to control the expression of specific detoxification pathways. In addition, the maintenance of the redox balance is crucial for survival of S.aureus under redox stress during infections, which is accomplished by the low molecular weight (LMW) thiol bacillithiol (BSH) and the associated bacilliredoxin (Brx)/BSH/bacillithiol disulfide reductase (YpdA)/NADPH pathway. Here, we present an overview of thiol-based redox sensors, its associated enzymatic detoxification systems and BSH-related regulatory mechanisms in S.aureus, which are important for the defense under redox stress conditions. Application of the novel Brx-roGFP2 biosensor provides new insights on the impact of these systems on the BSH redox potential. These thiol switches of S.aureus function in protection against redox active desinfectants and antimicrobials, including HOCl, the AGXX® antimicrobial surface coating, allicin from garlic and the naphthoquinone lapachol. Thus, thiol switches could be novel drug targets for the development of alternative redox-based therapies to combat multi-drug resistant S.aureus isolates.
Highlights
Staphylococcus aureus is a major human pathogen, which encounters reactive oxygen, nitrogen, chlorine, electrophile and sulfur species (ROS, RNS, RCS, reactive electrophilic species (RES) and reactive sulfur species (RSS)) by the host immune system, during cellular metabolism or antibiotics treatments
The maintenance of the redox balance is crucial for survival of S. aureus under redox stress during infections, which is accomplished by the low molecular weight (LMW) thiol bacillithiol (BSH) and the associated bacilliredoxin (Brx)/BSH/bacillithiol disulfide reductase (YpdA)/NADPH pathway
We present an overview of thiol-based redox sensors, its associated enzymatic detoxification systems and BSH-related regulatory mechanisms in S. aureus, which are important for the defense under redox stress conditions
Summary
S. aureus encodes several antioxidant enzymes, including superoxide dismutases (SODs), catalases and peroxiredoxins, which are involved in detoxification of ·O2 − and. SodM expression was upregulated in S. aureus in airway environments of cystic fibrosis patients (Treffon et al 2018) Both SodA and SodM are important for virulence in a murine abscess model and required for nutritional immunity in S. aureus, when Mn2+ is restricted in the host due to sequestering by calprotectin during infections (Garcia et al 2017; Gaupp et al 2012; Karavolos et al 2003; Kehl-Fie et al 2011). SodA is required for oxidative stress resistance and virulence in a murine infection model in the presence of Mn2+, while SodM is more important under Mn2+-starvation and provides resistance to nutritional immunity (Garcia et al 2017). Many other peroxiredoxins respond to oxidative stress, such as Tpx, Bcp or GpxA1 and GpxA2, which remain to be, characterized in future studies
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