UBC Theses and Dissertations
Combating Pseudomonas aeruginosa lung infections using synthetic host defense peptides Wuerth, Kelli
Pseudomonas aeruginosa is a Gram negative bacterium found frequently in the environment. It can infect immunocompromised patients and is a major cause of nosocomial infections. Of particular concern are its roles in lung infections as a causative agent for pneumonia and in respiratory infections in patients with cystic fibrosis and chronic obstructive pulmonary disease. Treatment of P. aeruginosa lung infections is difficult due to its formation of biofilms and the development of multi-drug resistant P. aeruginosa strains. Synthetic derivatives of host defense peptides (HDPs) called innate defense regulators (IDRs) are alternatives to antibiotics that modulate the immune response rather than directly targeting the bacteria, thus limiting the development of antibiotic resistance. IDRs have shown success against many bacteria but had not previously been tested in P. aeruginosa lung infection models. In this work, IDR-1002 reduced the production of inflammatory cytokines by macrophages in response to P. aeruginosa lipopolysaccharide. IDR-1002 also limited the toxicity caused by live P. aeruginosa to macrophages and bronchial epithelial cells. Importantly, IDR-1002 did not show any toxic effects in vitro, unlike the HDP LL-37. In an acute in vivo P. aeruginosa lung infection model, IDR-1002 significantly decreased the bacterial burden as well as the concentrations of MCP-1, KC, and IL-6 in the lungs. In another in vivo P. aeruginosa lung infection model using alginate to mimic a chronic infection, IDR-1002 decreased the infiltration of cells to the infection site and significantly decreased IL-6 levels in the lungs. To improve drug delivery, peptide IDR-1018, which has a strong aggregation propensity, was tested with various formulations, and its combination with a hyperbranched polyglycerol reduced the production of inflammatory cytokines in vitro and trended towards reducing cytokines in vivo in the acute P. aeruginosa lung infection model. Finally, RNA-Seq and downstream bioinformatics were performed on both lung and blood samples from the acute P. aeruginosa lung infection model, providing insights into the impact of P. aeruginosa during infection and the protective mechanisms of IDR-1002 via its anti-inflammatory effects. These data suggest the strong potential of IDR-1002 for the treatment of P. aeruginosa lung infections.
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