Development of New Therapeutics Targeting Biofilm Formation by the Opportunistic Pulmonary Pathogens Pseudomonas aeruginosa and Aspergillus fumigatus
Abstract
Major accomplishments this period: 1. All in vitro work (Major Task 1) was completed and demonstrated synergy between glycoside hydrolases (GHs) and a wide range of antimicrobials. 2. We completed studies of the tolerability and pharmacokinetics of GH enzymes (Major Task 2 and 3). GH variants (Major Task 4) were developed for Sph3, Ega3 and PelA, through chemical and genetic modifications to address issues of tolerability (Ega3) and short half-life in vivo (PelA, Sph3). Variants are currently being evaluated, but results to date indicate that these new variants exhibit similar enzymatic activity and pharmacokinetics but increased resistance to some commercial protease and decreased immunogenicity. 3. In an acute model of murine invasive aspergillosis, we completed studies of GH monotherapy and combination therapy, demonstrating that all GH treatment regimens resulted in significantly reduced pulmonary fungal burden (Major Task 5). Intra-tracheal Sph3 was also found to extend survival of immunosuppressed mice challenged with Aspergillus and further studies evaluating the effects of other GHs on survival are ongoing. Studies of GH therapy in the chronic model of invasive aspergillosis have been initiated (Major Task 6).
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2018
- Accession Number
- AD1064016
Entities
People
- Donald C Sheppard
Organizations
- McGill University Health Centre