Understanding mechanisms of virulence in MRSA: implications for antivirulence treatment strategies.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is a widespread pathogen, often causing recurrent and deadly infections in the hospital and community. Many S. aureus virulence factors have been suggested as potential targets for antivirulence therapy to decrease the threat of diminishing antibiotic availability. Antivirulence methods hold promise due to their adjunctive and prophylactic potential and decreased risk for selective pressure. AREAS COVERED: This review describes the dominant virulence mechanisms exerted by MRSA and antivirulence therapeutics that are currently undergoing testing in clinical or preclinical stages. We also discuss the advantages and downsides of several investigational antivirulence approaches, including the targeting of bacterial transporters, host-directed therapy, and quorum-sensing inhibitors. For this review, a systematic search of literature on PubMed, Google Scholar, and Web of Science for relevant search terms was performed in April and May 2023. EXPERT OPINION: Vaccine and antibody strategies have failed in clinical trials and could benefit from more basic science-informed approaches. Antivirulence-targeting approaches need to be set up better to meet the requirements of drug development, rather than only providing limited results to provide 'proof-of-principle' translational value of pathogenesis research. Nevertheless, there is great potential of such strategies and potential particular promise for novel probiotic approaches.

Extensive remodelling of the cell wall during the development of Staphylococcus aureus bacteraemia.

The bloodstream represents a hostile environment that bacteria must overcome to cause bacteraemia. To understand how the major human pathogen Staphylococcus aureus manages this we have utilised a functional genomics approach to identify a number of new loci that affect the ability of the bacteria to survive exposure to serum, the critical first step in the development of bacteraemia. The expression of one of these genes, tcaA, was found to be induced upon exposure to serum, and we show that it is involved in the elaboration of a critical virulence factor, the wall teichoic acids (WTA), within the cell envelope. The activity of the TcaA protein alters the sensitivity of the bacteria to cell wall attacking agents, including antimicrobial peptides, human defence fatty acids, and several antibiotics. This protein also affects the autolytic activity and lysostaphin sensitivity of the bacteria, suggesting that in addition to changing WTA abundance in the cell envelope, it also plays a role in peptidoglycan crosslinking. With TcaA rendering the bacteria more susceptible to serum killing, while simultaneously increasing the abundance of WTA in the cell envelope, it was unclear what effect this protein may have during infection. To explore this, we examined human data and performed murine experimental infections. Collectively, our data suggests that whilst mutations in tcaA are selected for during bacteraemia, this protein positively contributes to the virulence of S. aureus through its involvement in altering the cell wall architecture of the bacteria, a process that appears to play a key role in the development of bacteraemia.

Extensive re-modelling of the cell wall during the development of Staphylococcus aureus bacteraemia.

The bloodstream represents a hostile environment that bacteria must overcome to cause bacteraemia. To understand how the major human pathogen Staphylococcus aureus manages this we have utilised a functional genomics approach to identify a number of new loci that affect the ability of the bacteria to survive exposure to serum, the critical first step in the development of bacteraemia. The expression of one of these genes, tcaA, was found to be induced upon exposure to serum, and we show that it is involved in the elaboration of a critical virulence factor, the wall teichoic acids (WTA), within the cell envelope. The activity of the TcaA protein alters the sensitivity of the bacteria to cell wall attacking agents, including antimicrobial peptides, human defence fatty acids, and several antibiotics. This protein also affects the autolytic activity and lysostaphin sensitivity of the bacteria, suggesting that in addition to changing WTA abundance in the cell envelope, it also plays a role in peptidoglycan crosslinking. With TcaA rendering the bacteria more susceptible to serum killing, while simultaneously increasing the abundance of WTA in the cell envelope, it was unclear what effect this protein may have during infection. To explore this, we examined human data and performed murine experimental infections. Collectively, our data suggests that whilst mutations in tcaA are selected for during bacteraemia, this protein positively contributes to the virulence of S. aureus through its involvement in altering the cell wall architecture of the bacteria, a process that appears to play a key role in the development of bacteraemia.

Identification and characterization of the pathogenic potential of phenol-soluble modulin toxins in the mouse commensal Staphylococcus xylosus.

In contrast to the virulent human skin commensal Staphylococcus aureus, which secretes a plethora of toxins, other staphylococci have much reduced virulence. In these species, commonly the only toxins are those of the phenol-soluble modulin (PSM) family. PSMs are species-specific and have only been characterized in a limited number of species. S. xylosus is a usually innocuous commensal on the skin of mice and other mammals. Prompted by reports on the involvement of PSMs in atopic dermatitis (AD) and the isolation of S. xylosus from mice with AD-like symptoms, we here identified and characterized PSMs of S. xylosus with a focus on a potential involvement in AD phenotypes. We found that most clinical S. xylosus strains produce two PSMs, one of the shorter α- and one of the longer ß-type, which were responsible for almost the entire lytic and pro-inflammatory capacities of S. xylosus. Importantly, PSMα of S. xylosus caused lysis and degranulation of mast cells at degrees higher than that of S. aureus δ-toxin, the main PSM previously associated with AD. However, S. xylosus did not produce significant AD symptoms in wild-type mice as opposed to S. aureus, indicating that promotion of AD by S. xylosus likely requires a predisposed host. Our study indicates that non-specific cytolytic potency rather than specific interaction underlies PSM-mediated mast cell degranulation and suggest that the previously reported exceptional potency of δ-toxin of S. aureus is due to its high-level production. Furthermore, they suggest that species that produce cytolytic PSMs, such as S. xylosus, all have the capacity to promote AD, but a high combined level of PSM cytolytic potency is required to cause AD in a non-predisposed host.

Investigational agents for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia: progress in clinical trials.

INTRODUCTION: Bacteremia caused by Staphylococcus aureus is common. Cases caused by methicillin-resistant S. aureus (MRSA) are particularly formidable and often lethal. The mortality associated with MRSA bacteremia has not significantly decreased over the past couple of decades and concerns regarding efficacy and toxicity of standard therapy highlight the need for novel agents and new therapeutic approaches. AREAS COVERED: This paper explores clinical trials investigating novel therapeutic approaches to S. aureus bacteremia. There is a special focus on MRSA bacteremia. Monotherapy and combination therapies and novel antimicrobials and adjunctive therapies that are only recently being established for therapeutic use are discussed. EXPERT OPINION: The unfavorable safety profile of combination antimicrobial therapy in clinical trials has outweighed its benefits. Therefore, future investigation should focus on optimizing duration and de-escalation protocols. Antibody and bacteriophage lysin-based candidates have mostly been limited to safety trials, but progress with these agents is demonstrated through a lysin-based agent receiving a phase III trial. Antibiotics indicated for use in treating MRSA skin infections see continued investigation as treatments for MRSA bacteremia despite the difficulty of completing trials in this patient population. Promising agents include dalbavancin, ceftobiprole, ceftaroline, and exebacase.