Attack is the Best Form of Defense: Finding New Ways to Target Cystic Fibrosis Bacteria

Many of us know that cystic fibrosis is a genetic disorder characterized by enduring and debilitating lung infections. What may be less well-known is that the main pathogen involved in these lung infections is Pseudomonas aeruginosa, a bacteria capable of causing significant morbidity and mortality in people with cystic fibrosis.

To date, there is no known cure for cystic fibrosis, and effective treatments that can specifically target P. aeruginosa are urgently needed. Before this can happen, we must first understand the cellular mechanisms that drive the bacteria’s ability to cause infection.

This is where new research from the Department of Molecular and Cellular Biology comes in. Dr. Cezar Khursigara recently led a study to uncover how different P. aeruginosa are virulent using one key cellular structure: peptidoglycan.

Peptidoglycan is a structure in bacterial cell walls that consists of repeating units of peptides (protein building blocks) and polysaccharides (large carbohydrate molecules) that serves critical functions, like providing cellular structure and defense.

“The structure of peptidoglycan is flexible but very strong, like a coat of armour,” says Khursigara. “Understanding the peptidoglycan layer can allow us to indirectly understand the specific structures responsible for the cell’s defense system, and potentially give us specific drug or vaccine targets.”

Khursigara and his team of undergraduate and graduate students first compared the peptidoglycan structures from two types of P. aeruginosa strains: laboratory strains, which are less transmissible, less resistant to antimicrobials, and thus does not infect people as readily; and epidemic strains, which are more transmissible, more resistant to antimicrobials, and thus more pathogenic. They also compared the peptidoglycan from these strains cultured in standard lab conditions versus a synthetic cystic fibrosis medium, composed of nutrients intended to mimic the environmental conditions of the disorder.

A surprising finding to emerge from the study is that the nutrient conditions P. aeruginosa grow in affects the composition of peptidoglycan, highlighting the complex relationship between the bacterium’s structure and its growing environment.

“Historically, peptidoglycan has been thought to be a rigid and conserved structure,” says Khursigara, “but we discovered that it is more diverse and dynamic than other studies have let on.”

The researchers were also surprised to identify, across all P. aeruginosa strains, 448 unique peptide structures associated with the cell wall. They identified significantly more of these peptides than previously seen, providing important insight into the inner workings of the bacterium’s “armour”.

Khursigara’s lab used innovative methods to identify and analyze these structures. This enabled the identification and comparison of hundreds of cell wall peptides at once across different samples, providing a far more comprehensive understanding of how the cystic fibrosis environment affects peptidoglycan formation in P. aeruginosa than previously seen.

This exciting research is the first step towards the development of antibiotics and vaccines that target P. aeruginosa peptidoglycan. But this research isn’t just applicable to cystic fibrosis treatments– there are potential industrial and agricultural applications related to contaminated crops, livestock, and equipment, too.  

This study also contributes to the University of Guelph’s One Health approach to solving major health issues involving humans, animals, and the environment.

“The University takes a One Health approach to tackling antimicrobial resistance, from farms to hospitals to what we do as a society. We’re glad our research can be a piece of the puzzle fitting into this larger framework of research,” says Khursigara.

Future research in the lab aims to investigate if peptidoglycan makes P. aeruginosa more resistant to antibiotics and test the effectiveness of new antibiotics for cystic fibrosis.

Read the full study in the journal American Society for Microbiology.

Read about other CBS Research Highlights.