Preclinical Evaluation of Recombinant Microbial Glycoside Hydrolases as Antibiofilm Agents in Acute Pulmonary Pseudomonas aeruginosa Infection
Hanna Ostapska, Deepa Raju, Rachel Corsini, Mélanie Lehoux, Ira Lacdao, Stephanie Gilbert, Piyanka Sivarajah, Natalie C. Bamford, Perrin Baker, Fabrice N. Gravelat, P. Lynne Howell, Donald C. Sheppard
Abstract
The bacterium Pseudomonas aeruginosa can colonize the airways of patients with chronic lung disease. Within the lung, P. aeruginosa forms biofilms that can enhance resistance to antibiotics and immune defenses. P. aeruginosa biofilm formation is dependent on the secretion of matrix exopolysaccharides, including Pel and Psl. In this study, recombinant glycoside hydrolases (GHs) that degrade Pel and Psl were evaluated alone and in combination with antibiotics in a mouse model of P. aeruginosa infection. Intratracheal GH administration was well tolerated by mice. Pharmacokinetic analysis revealed that, although GHs have short half-lives, administration of two GHs in combination resulted in increased GH persistence. Combining GH prophylaxis and treatment with the antibiotic ciprofloxacin resulted in greater reduction in pulmonary bacterial burden than that with either agent alone. This study lays the foundation for further exploration of GH therapy in bacterial infections.