Project description:In many pathogens, quorum-sensing systems regulate virulence. Quorum-sensing is therefore often proposed as a target for antivirulence drug development. Coagulase-negative staphylococci are leading causes of nosocomial blood infections and of mortality due to sepsis as the most extreme consequence of such infections. However, there is a severe lack of understanding how virulence and especially quorum-sensing affects coagulase-negative staphylococcal sepsis. Using a mouse systemic infection model, we here show that the staphylococcal Agr quorum-sensing system has a strong impact on mortality from sepsis caused by the exemplary coagulase-negative staphylococcal species Staphylococcus haemolyticus. To that end, we analyzed the mechanism and regulon of S. haemolyticus Agr, which revealed a strong focus of quorum-sensing regulation of phenol-soluble modulin toxins. Our results further indicate that PSMs are the virtually exclusive mediators of the Agr effect on S. haemolyticus sepsis and suggest that the predominant underlying mechanism is cytolytic capacity of PSMs. These findings imply that Agr and PSMs represent promising targets for antivirulence drug development targeting sepsis caused by coagulase-negative staphylococci. This contrasts quorum-sensing targeted efforts to control S. aureus blood infections, for which such approaches are considered less promising - a difference our results suggest is due to the much more focused role of Agr control in coagulase-negative staphylococci, where among toxins, Agr exclusively and exceptionally tightly controls PSMs.
Project description:Staphylococcus epidermidis is a Gram-positive, coagulase-negative (CoNS) bacterium that is carried asymptomatically on the skin and mucous membranes of virtually all human beings. It is a major cause of nosocomial infections and associated with invasive procedures (Méric et al., 2018). Virulent S. epidermidis strains contaminate indwelling medical devices, such as catheters or implants (Sabaté Brescó et al., 2017), showing pathogenicity traits, e.g., biofilm formation, cell toxicity, or methicillin resistance (Méric et al., 2018). Apart from that, even the low-virulent, low-biofilm forming strain of S. epidermidis ATCC 12228 was shown to form a biofilm under decreased oxygen conditions (Uribe-Alvarez et al., 2015). As a member of the skin and mucosal microbiome, S. epidermidis prevents the colonization of Staphylococcus aureus (Otto, 2011). Its well-studied metabolism and the ability to grow on known media make S. epidermidis a possible reconstruction candidate. A reconstruction of a genome-scale metabolic model (GEM) of S. epidermidis was created using CarveMe (Machado et al., 2018) and carefully refined in subsequent manual curation efforts, using the S. epidermidis ATCC 12228 strain sequence. The model was experimentally validated on multiple media under varying growth conditions, such as different carbon sources.
Project description:Staphylococcus pseudintermedius, Staphylococcus coagulans and coagulase-negative staphylococci cultured from clinical canine skin and ear samples in Queensland
Project description:Staphylococcus haemolyticus is a skin commensal emerging as an opportunistic pathogen. Nosocomial isolates of S. haemolyticus are the most antibiotic resistant members of the coagulase negative staphylococci (CoNS), but information about other S.haemolyticus virulence factors is scarce. Bacterial virulence is mediated by membrane vesicles (MVs) which enable secretion and long distance delivery of bacterial effector molecules while protecting the cargo from proteolytic degradation from the environment. We wanted to determine if the MV protein cargo of S.haemolyticus is strain specific and enriched in certain MV associated proteins compared to the totalsecretome. The present study shows that both clinical and commensal S. haemolyticus isolates produce membrane vesicles. The MV cargo of both strains was enriched in proteins involved in adhesion and in acquisition of iron. The MV cargo of the clinical strain was further enriched in antimicrobial resistance proteins.