Thiol-based redox switches in the major pathogen Staphylococcus aureus

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.

The Role of ArlRS and VraSR in Regulating Ceftaroline Hypersusceptibility in Methicillin-Resistant Staphylococcus aureus

“…ArlRS has been described as a global regulator of S. aureus virulence, extracellular proteases, capsule formation, and is a direct regulator of mgrA [18]. The extensive and complex ArlRS regulon, which displays a 70% overlap with the redoxsensitive MgrA regulon [19,20], indicates that it might be difficult to pinpoint a particular ArlRS-dependent function that precisely explains our observed ceftaroline hypersensitivity. Nevertheless, a predicted ArlR binding site was shown in the Spx promoter region.…”

Repurposing Eltrombopag for Multidrug Resistant Staphylococcus aureus Infections

“…Base insertion or deletion mutations occurred in the other three genes including yjbH , lytE , and yokF , which likely cause complete loss of their functions resulted from protein truncation. Since the abnormal presence of autolysins and endonucleases such as LytE and YokF can cause bacterial death and these enzymes were found to be impaired in the eltrombopag resistant clones, it implies that eltrombopag-mediated bacterial growth inhibition might be associated with the activity of LytE and YokF [ 16 , 17 ]. The mutation of yjbH found in the resistant mutants likely results in decreased degradation of Spx, a stress response gene regulator suggesting the pivotal role of the stress response for the bacterial resistance of eltrombopag [ 18 ].…”

Understanding the Role of the Antioxidant Drug Erdosteine and Its Active Metabolite on Staphylococcus aureus Methicillin Resistant Biofilm Formation

“…Hmp expression is strictly controlled by the staphylococcal respiratory regulator (SrrAB), a two-component redox sensor that is implicated, among others, in long-term biofilm stability [ 53 ]. Indeed, NO leads to the activation of the SrrAB, which controls expression of hmp [ 54 ]. This process is essential for S. aureus bacterial colonization and biofilm development as well antibiotic and nitrosative stress resistance.…”