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Spotlight on Research

ANTIBIOTIC TOLERANCE IN PSEUDOMONAS AERUGINOSA: HOW CAN ANTIBIOTICS BE MORE EFFECTIVE IN THE TREATMENT OF CHRONIC PSEUDOMONAS INFECTION?

Q&A WITH DR. DAO NGUYEN
Associate Professor, McGill University

How did you become involved in cystic fibrosis research and what do you enjoy most about your work?

I started working in CF research during my post-doctoral training in Seattle where I became captivated by the scientific questions related to CF microbiology as well as the collaborative and multidisciplinary nature of CF research. The CF research and patient community has inspired me by their commitment and vision, and I have been doing CF -related research since then.   

As a clinician-scientist, I am privileged to work both in the clinical and research world, and these two facets make my work highly stimulating, meaningful (and busy!). As a respirologist, I take care of patients with lung disease, including cystic fibrosis, and my clinical practice provides me a real-world view of the needs and challenges of patients and their families. I value my time with patients, being able to provide care and help them navigate complex health issues. My clinical work also leaves me with lots of questions, and my research allows me to tackle some of these questions.

Patients with cystic fibrosis suffer from lifelong lung infections which cause their symptoms and lung function to worsen. This has motivated me and my group to study various aspects of Pseudomonas biology and host interactions that could help better understand CF lung infections and develop future anti-infective treatments. What I enjoy most about my research is the quest to solve problems, the lifelong learning and use of new scientific techniques, the opportunity to train the next generation of scientists and to work with wonderful colleagues who share the same passion. 

Please tell us about your latest findings?

Even though we now know that lung infections in CF patients are complex, Pseudomonas aeruginosa remains a major challenge as it is the main pathogen and major target of antibiotics used in adult CF patients. Unfortunately, antibiotics are not as effective at killing this bacterium once chronic infection has set in, even when the bacteria is not considered “resistant” to antibiotics when tested by the hospital microbiology laboratory.

We and others believe that an important reason why antibiotics are much less effective than they should be in the treatment of chronic infection is because Pseudomonas adopts an antibiotic tolerant state. This refers to a drug “indifferent” state where bacteria survive the toxic effects of antibiotics (often to multiple classes of antibiotics). Scientist have known for a long time that bacteria, when they run out of nutrients (in a test tube, in the host or in a biofilm), slow down their growth and become highly antibiotic tolerant. Despite this being a long-standing observation, remarkably little is known about the mechanisms of tolerance.

My group has been investigating the mechanisms that confers antibiotic tolerance to Pseudomonas and recently discovered a new function for a signaling system (termed the stringent response) and superoxide dismutases (an anti-oxidant defense enzyme). We found that Pseudomonas, when it is under stress or lacking nutrients, adapts to this stress by modifying its cell membranes to make it less permeable. Since the cell membrane serves as a barrier that prevents drugs (including antibiotics) from penetrating inside the cell, we showed that slow growing Pseudomonas becomes tolerant to antibiotics by altering the permeability of its cell membrane, and this adaptive change requires the function of the stringent response signaling and activity of superoxide dismutases. 

What does this mean for people living with CF?

Our findings are still very fundamental and not yet readily applicable to treatments for CF patients. However, understanding these basic mechanisms is critical for the development of future therapies. We know very little about the cell functions that are important to tolerance and how to overcome tolerance, and hope that our findings will help identify new strategies to improve the effectiveness of our current antibiotics.

What are the next steps in your research?

We want to better define the molecular mechanisms that make the cell membranes of non-growing cells highly impermeable and to identify potential targets for “anti-tolerance” therapies. We have promising leads and hope that this will get us and others closer to new anti-infective therapies for CF patients.

 

Bio:

Dao Nguyen is an associate professor in the Department of Medicine at McGill University, a scientist at both the Research Institute of the McGill University Health Centre and Meakins Christie Laboratories, and a clinician-scientist in the Division of Respiratory Medicine at the McGill University Health Centre. Her research is focused on CF microbiology, particularly the molecular microbiology of Pseudomonas aeruginosa, antibiotic tolerance and biofilms, as well as host-pathogen interactions in CF pulmonary infections. She is the recipient of a CF Canada grant, CIHR Clinician scientist award, and Burroughs Wellcome Fund Career Award for Medical Scientist.