Staphylococcus aureus is an opportunistic human pathogen that can cause life-threatening infections, like septicemia, endocarditis and necrotizing pneumonia. In addition, nosocomial infections are often caused by multiple antibiotic resistant strains, such as methicillin-resistant S. aureus (MRSA). During infections, S. aureus has to cope with reactive oxygen and electrophile species (ROS, RES), such as hydrogen peroxide (H2O2), the strong oxidant hypochloric acid (HOCl), quinones and aldehydes. The success of the pathogen is mediated by efficient protection mechanisms against the host immune defence, including the bacillithiol (BSH) redox buffer, redox-sensing virulence regulators and antioxidant enzymes, such as catalases and peroxidases.
This project will investigate priming and memory mechanisms in response to oxidative and electrophile stress in S. aureus. The goals of this project are to understand the molecular mechanisms of priming S. aureus for improved resistance against different infection-relevant redox-active compounds, including ROS (H2O2), HOCl and RES (quinones, methylglyoxal, formaldehyde). We are further interested in elucidating if priming of S. aureus by ROS, HOCl and RES can confer cross-protection against other redox-active compounds. S. aureus is also known for its remarkable H2O2 resistance, which is attributed to constitutive expression of catalase. The molecular mechanisms regulating this high catalase expression and peroxide resistance will be investigated in this project.
We have recently studied the specific responses to ROS and RES in S. aureus and already identified stress-specific regulons and their main regulators that confer resistance to these stressors. We hypothesise that major redox-regulators, such as SarZ, MgrA, SarA and PerR play important roles in memory of oxidative stress provoked by hypochlorite and peroxide stress, as well as in priming for improved resistance against these stressors. We further plan to characterise the role of the novel NaOCl-sensing redox regulator HypR and the HypR-controlled pyridine nucleotide disulfide oxidoreductase MerA in ROS and NaOCl priming in S. aureus. Previous studies also suggest that the quinone-specific QsrR and MhqR regulons are involved in priming S. aureus for improved quinone resistance. This suggestion will be investigated in more detail. The function, structure and mechanism of the novel MhqR regulator of S. aureus in regulation of quinone resistance will be elucidated. Moreover, we identified HxlR as novel aldehyde-specific redox-sensor that controls the aldehyde-inducible aldehyde dehydrogenase AldA in S. aureus. We aim to study the roles of HxlR and AldA in methylglyoxal and formaldehyde priming, detoxification and resistance. Finally, the effect of the different redox-sensing regulators, that regulate ROS and RES priming, will be tested in infection assays in vivo to validate our hypothesis that priming contributes to pathogenicity of S. aureus.
Taken together, these studies on ROS and RES priming are directed to understand the adaptation of S. aureus to the host defence under infection conditions and to identify possible drug targets required for priming and fitness of the pathogen. The discovery of targets for the development of novel antibiotics is of utmost importance for the successful treatment of emerging MRSA infections.