Summary
Researchers at Western University have identified a mutations in S. aureus purine biosynthesis pathway that contribute to its virulence. The current invention opens up alternate treatment and target mechanisms for hard to treat S. aureus and MRSA.
Background
In humans, Staphylococcus aureus may exist as a commensal bacterium or as a pathogen. Data from the United States Centers for Disease Control and Prevention show that approximately one-third of the US population is colonized with S. aureus, and colonization with S. aureus is associated with increased risk of subsequent infection. Infections caused by S. aureus range in severity from relatively minor skin and soft tissue infections through to invasive diseases such as pneumonia, infective endocarditis and osteomyelitis. Strikingly, the magnitude of morbidity and mortality caused by S. aureus is highlighted by reports that, in the US, invasive infections by this bacterium cause more deaths than HIV.
Despite a wealth of knowledge on virulence regulation in S. aureus, there are still outstanding questions to be resolved, as novel mechanisms of virulence regulation are still being discovered, especially with regard to environmental or metabolic cues to which S. aureus responds.
Technology Overview
Researchers at Western University have identified a mutations in S. aureus purine biosynthesis pathway that contribute to its virulence. The function of the purR gene in S. aureus has not been characterized. Inactivating mutations in purR caused S. aureus to become highly virulent in mouse models of infection
The current discovery demonstrates that purR mutations have a heretofore undescribed role in regulating expression of S. aureus fibronectin binding proteins and, thus, play a role in the interaction of S. aureus with fibronectin.
In the absence of anti-FnbA/B antibodies, purR mutants clump vigorously in serum in a fibronectin-dependent manner. Importantly, purR mutants, also through FnbA/B-dependent mechanisms, are hypervirulent in a systemic model of infection in mice, and vaccination of mice against FnbA/B can diminish hypervirulence and ameliorate animal mortality.
The current invention proposes that, in S. aureus, PurR is critical to limit the expression of fnb genes, known to be maximally expressed at low cell density, in order to promote colonization, yet prevent cell clumping in the vasculature.
Benefits and Applications
• Solution to difficult to treat infections by Staphylococcus aureus or MRSA.
• Identification of small molecule or targets to attenuate Staphylococcus aureus virulence.
• Vaccine development for Staphylococcus aureus.
• Treatment methods for Staphylococcus aureus infections.
Publications
Goncheva, Mariya I., et al. "Stress-induced inactivation of the Staphylococcus aureus purine biosynthesis repressor leads to hypervirulence." Nature Communications 10.1 (2019): 775.
https://www.nature.com/articles/s41467-019-08724-x
Western News Article March 2019
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