Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Dr. Ruud Veldhuizen

2nd Supervisor

Dr. Cory Yamashita

Joint Supervisor

Abstract

Bacterial pneumonia, one of the leading causes of hospitalization and mortality worldwide, is caused by the colonization of invasive bacteria in the airways, leading to pulmonary inflammation and lung dysfunction. The development of antibiotic resistant bacterial infections has limited the effectiveness of current therapeutics and is particularly concerning in the setting of chronic bacterial infections, such as observed in cystic fibrosis and ventilator-associated pneumonia. The development of novel therapeutics for the treatment of multi-drug resistant bacterial pneumonia is urgently needed.

The overall objective of this body of work was the development of a new therapeutic compound to treat multi-drug resistant bacterial infections in the lung. It was hypothesized that a cathelicidin/exogenous surfactant compound could be developed as a novel therapeutic agent for the treatment of bacterial pneumonia. To test this hypothesis, we first screened several cathelicidin peptides combined with a commercial exogenous surfactant, bovine lipid extract surfactant (BLES), and identified a lead compound (CATH-2) for further testing. Following this, we investigated three main outcomes: 1) the antimicrobial activity of CATH-2 and BLES+CATH-2 against multi-drug resistant, clinically isolated bacteria; 2) the immunomodulatory potential of both CATH-2 and BLES+CATH-2 in vivo; and 3) the bactericidal activity of BLES+CATH-2 treatment in vivo, using two models of bacterial pneumonia.

It was discovered that CATH-2 was able to kill bacteria in vitro. In addition, CATH-2 killed bacteria administered into the lungs of mice did not induce an inflammatory response in vivo, and that the ability to prevent this inflammation was maintained by BLES+CATH-2. Finally, while BLES+CATH-2 is able to kill multi-drug resistant, clinically derived bacteria in vitro, there is little bactericidal activity of BLES+CATH-2 in in vivo models of bacterial pneumonia.

Overall, we identified the therapeutic potential of BLES+CATH-2 for use as a therapeutic treatment for bacterial pneumonia. Despite promising in vitro activity, we were unable to show bactericidal activity for BLES+CATH-2 in vivo. Future directions will require the optimization of the surfactant-cathelicidin compound in order to develop a viable therapeutic for clinical practice.


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