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Development of New Therapeutics Targeting Biofilm Formation by the Opportunistic Pulmonary Pathogens Pseudomonas Aeruginosa and Aspergillus Fumigatus


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The bacterium Pseudomonas aeruginosa and fungus Aspergillus fumigatus are common causes of pulmonary disease in immunocompromised patients. During infection, both organisms form biofilms making them resistant to both antimicrobials and the immune system. This biofilm formation is dependent on exopolysaccharide synthesis. We have previously shown that the glycoside hydrolases (GH) PelA, PslG, Sph3 and Ega3 disrupt P. aeruginosa and A. fumigatus biofilms in vitro. In this project we have (i) optimized the production endotoxin free GHs to increase yields significantly; (ii)identified antimicrobials that are potentiated by the GHs in vitro; (iii) demonstrated that intratracheal administration of the 4 GHs in mice is well tolerated; (iv) determined the half-life of each GH alone or in combination in vivo; (v) demonstrated that GHs can mitigate infection both alone and in combination with antifungals in an acute model of invasive aspergillosis; and (vi) demonstrated potentiation of the antibiotic ciprofloxacin when a combination of PslG/PelA was co administered in a P. aeruginosa model of mouse infection. In summary, the results generated demonstrate that treatment with GHs alone or in combination with antimicrobials could significantly improve outcomes of pulmonary infections.



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