Eradication of in Vivo Staphylococcus aureus Biofilms with Lysin CF-301
Abstract
Healthcare-associated infections (HAI) include central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and surgical site infections. In clinical medicine, it is estimated that 65%-80% of all infections are biofilm-associated. Biofilms are aggregates of microorganisms in which cells are embedded within a self-produced matrix. Biofilms pose a unique therapeutic challenge because bacteria within the biofilm matrix exhibit high levels of antibiotic tolerance. Thus, the treatment of biofilm infections represents a major unmet medical need, requiring novel drugs to eradicate biofilm-associated infections. ContraFect s first-in-class bacteriophage lysin, CF-301, is an enzyme that cleaves target bacteria cell walls. CF-301 displays potent activity against Staphylococcus aureus, and is currently in clinical development for the treatment of serious or life-threatening bloodstream infections caused by methicillin-susceptible and -resistant S. aureus. Preliminary data support the development of CF-301 for MRSA (methicillin-resistant S. aureus) biofilm-based infections. The objective of this proposal, addressing Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area: Healthcare-Acquired Infection Reduction, is to identify the optimal way to dose CF-301 in combination with standard of care antibiotics such as daptomycin. This proposal is based upon the hypothesis that administration of a single-dose of CF-301 is sufficient to disrupt S. aureus biofilms and that administration of CF-301 in combination with daptomycin, an antibiotic agent currently used in the clinic for systemic and life-threatening Gram-positive infections, will eradicate MRSA biofilm-based infections in vivo. Additionally, we will test a hypothesis that the mechanism of synergy between CF-301 and daptomycin is based on the disruption of biofilm extracellular matrix by CF-301, increasing the permeability of daptomycin into the biofilm. Experiments proposed will test the activity of CF-301, alone and in combination with daptomycin, against MRSA biofilms in rabbit left ventricular heart chamber inner lining infection (endocarditis) and mouse bone infection (osteomyelitis) models. Experiments will alter whether CF-301 is administered as a single dose, or fractionated over a longer period of time, to assess which regimen results in the greatest efficacy against MRSA biofilm-associated infections. Analyses will include assessments of animal health and disease progression, quantification of the bacterial burden within the biofilm infections, and visualization of the biofilm by high powered microscopy. Additionally, for the rabbit studies, we will utilize an innovative imaging approach to quantify and visualize the biofilm in and around the heart valve over time in a live animal, during and post-treatment. Results of this study will demonstrate CF-301 activity against diverse S. aureus biofilms in vivo, identify the optimal clinical CF-301 dosing regimen in combination with daptomycin for biofilm-based indications, and provide the rationale for advanced development of CF-301 for biofilm infections.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610245
Entities
People
- Raymond Schuch
Organizations
- United States Army