Research Interests:

General interest
Bacterial stress responses as determinants of antibiotic resistance and targets for therapeutic intervention

Specific interest
Oxidative stress-promoted antibiotic resistance in Pseudomonas aeruginosa causing chronic lung infections 


Background

P. aeruginosa is a Gram-negative opportunistic human pathogen associated with debilitating infections of immunocompromised individuals including those with HIV/AIDS cancer and severe burns, although it also causes less severe infections of healthy individuals (e.g., swimmers ear and hot tub folliculitis).  A common nosocomial (i.e., hospital-acquired) pathogen linked to infections of the blood, lungs and urinary tract, particularly in very sick individuals (e.g., those in the ICU), P. aeruginosa is a major pulmonary pathogen in patients with cystic fibrosis and chronic obstructive pulmonary disease and a major cause of ventilator-associated pneumonias.  Infections caused by P. aeruginosa have a high mortality rate, in part attributable to the organism’s intrinsically high resistance to many antimicrobials and the increased incidence of multidrug-resistant isolates in health care settings, both of which complicate antipseudomonal chemotherapy. 

Patients with cystic fibrosis (CF) are susceptible to pulmonary infections caused by many microorganisms, particularly Pseudomonas aeruginosa, which infects 80% of CF patients.  Such infections typically become chronic and lead to death, making P. aeruginosa lung infection the leading cause of mortality in CF.  Historically, CF patients colonized with P. aeruginosa have been treated with a combination of antibiotics, bronchodilators and chest physiotherapy. β-lactams and/or aminoglycosides have been the antibiotics of choice though in recent years these have been augmented by the fluoroquinolones.  Despite earlier concerns with toxicity, colistin is gaining favour, particularly in the treatment of multidrug-resistant P. aeruginosa infections.   Still, aminoglycosides remain the most significant class of antibiotic used in the treatment of CF lung infections.  Unfortunately, the need for ongoing and/or recurring treatment of chronic lung infections in CF patients contributes to the rise of antibiotic resistance in P. aeruginosa in the CF lung.

Primary objective
To characterize the stress adaptive mutations driving antibiotic resistance development in chronic lung infections of Pseudomonas aeruginosa in order to development suitable anti-resistance approaches to managing these infections.

Overview
Chronic pulmonary infections in cystic fibrosis and bronchiectasis patients caused by P. aeruginosa are major causes of human morbidity and mortality. Unfortunately, treatment of these infections is complicated by the increase in antibiotic resistance that develops during long-term colonization of the lung by this organism. Recent evidence suggests that this resistance derives, not from the usual acquired resistance mechanisms but from the accumulation of a unique set of adaptive mutations that are primarily intended to enhance the organism’s fitness at the site of infection but which also promote resistance. A hallmark of chronic P. aeruginosa lung infection is dysregulated pulmonary inflammation leading to release of reactive oxygen species (ROS) and, ultimately, chronic lung oxidative (O2) stress. In the case of chronic infections of the lungs of cystic fibrosis (CF) patients, this appears to be a driving force for the development of resistance to the aminoglycosides (AGs), an important class of anti-pseudomonal agent, with many AG resistance-promoting mutations having demonstrable links to O2 stress. Chronic P. aeruginosa infection in bronchiectasis patients is also associated with ongoing inflammation and chronic O2 stress, with AG resistance also a problem in these isolates. Thus, ROS/lung inflammation may be a driving force for AG resistance in these isolates as well and, thus, in P. aeruginosa causing chronic lung infections generally. The goals of my work are to define the contributions of these O2 stress-adaptive mutations to AG resistance in CF and bronchiectasis isolates of P. aeruginosa and to identify the resistance mechanisms involved, with an eye to targeting these latter therapeutically in an effort to maintain AG efficacy in managing chronic P. aeruginosa lung infections.

Sponsors
Canadian Institutes of Health Research and Cystic Fibrosis Canada