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Published on: May 8, 2013
Phage activity against Staphylococcus aureus is impaired in plasma and synovial fluid
Michele Mutti1, David Sáez Moreno1, Marcela Restrepo-Córdoba1
1BioNTech R&D Austria GmbH, Vienna, Austria.
Abstract:
S. aureus is a pathogen that frequently causes severe morbidity and phage therapy is being discussed as an alternative to antibiotics for the treatment of S. aureus infections. In this in vitro and animal study, we demonstrated that the activity of anti-staphylococcal phages is severely impaired in 0.5% plasma or synovial fluid. Despite phage replication in these matrices, lysis of the bacteria was slower than phage propagation, and no reduction of the bacterial population was observed. The inhibition of the phages associated with a reduction in phage adsorption, quantified to 99% at 10% plasma. S. aureus is known to bind multiple coagulation factors, resulting in the formation of aggregates and blood clots that might protect the bacterium from the phages. Here, we show that purified fibrinogen at a sub-physiological concentration of 0.4 mg/ml is sufficient to impair phage activity. In contrast, dissolution of the clots by tissue plasminogen activator (tPA) partially restored phage activity. Consistent with these in vitro findings, phage treatment did not reduce bacterial burdens in a neutropenic mouse S. aureus thigh infection model. In summary, phage treatment of S. aureus infections inside the body may be fundamentally challenging, and more investigation is needed prior to proceeding to in-human trials.
Insights
Phage therapy effectiveness against Staphylococcus aureus is hindered by plasma and synovial fluid, which impair phage activity and bacterial lysis. Further research is crucial before human trials for phage treatment of S. aureus infections.
Area of Science:
- Microbiology
- Infectious Diseases
- Biotechnology
Background:
- Staphylococcus aureus (S. aureus) infections cause significant illness.
- Phage therapy is a potential alternative to antibiotics for S. aureus.
- Understanding phage efficacy in vivo is critical.
Purpose of the Study:
- To investigate the impact of host biological fluids on anti-S. aureus phage activity.
- To elucidate the mechanisms behind phage inhibition in plasma and synovial fluid.
- To evaluate phage therapy efficacy in a preclinical S. aureus infection model.
Main Methods:
- In vitro assays assessing phage activity in plasma and synovial fluid.
- Quantification of phage adsorption to S. aureus in the presence of plasma.
- In vivo efficacy study using a neutropenic mouse model of S. aureus thigh infection.
- Investigation of fibrinogen's role and tissue plasminogen activator (tPA) intervention.
Main Results:
- Anti-S. aureus phage activity was severely impaired in 0.5% plasma and synovial fluid.
- Phage adsorption was reduced by up to 99% in 10% plasma.
- Fibrinogen at 0.4 mg/ml inhibited phage activity; tPA partially restored it.
- Phage treatment failed to reduce bacterial burden in a mouse infection model.
Conclusions:
- Host biological fluids, particularly plasma components like fibrinogen, significantly inhibit anti-S. aureus phage efficacy.
- Mechanisms involve impaired phage adsorption and potentially clot formation.
- Current phage therapy approaches may face fundamental challenges for treating S. aureus infections in vivo.
- Further investigation is required before clinical translation.
