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Trust-funded research identifies a new approach to treating Pseudomonas aeruginosa lung infections
Pseudomonas aeruginosa (P. aeruginosa) is the most common lung infection for adults with CF, and though it can be cleared or controlled if detected early, it can become antibiotic-resistant and develop into a long-term infection. Antibiotic-resistant strains of P. aeruginosa are a World Health Organisation (WHO) ‘priority 1 pathogen’, which means it poses one of the greatest threats to human health, and is in urgent need of new antibiotics and treatments.
Breaking down fat for energy
In order to grow and survive bacteria need an energy supply, and for the bacteria P. aeruginosa, the main energy supply comes from breaking down long molecules called fatty acids. However, little is known about the enzymes that break down fatty acids in these bacteria. If these enzymes could be blocked, this may be a way of preventing serious infections.
For the first time, Professor Martin Welch and colleagues identified which key enzymes are involved in breaking down fatty acids in P. aeruginosa and gained a detailed understanding of how they work. They showed that preventing the enzymes from working does reduce the levels of infection in the lab. Finally, they generated early data showing that chemicals could be designed to block these enzymes.
“We know that one of the main reasons why P. aeruginosa colonises the CF airways is because they are packed full of fatty acids, and P. aeruginosa loves fatty acids. However, the key enzymes involved in breaking these compounds down have eluded us for many years. In this work, and with the generous support of the Trust, we used state-of-the-art approaches to identify these enzymes, and show that indeed, they play an important role in infection. We also show that the enzymes can be inhibited by small molecules, opening the way towards targeting the pathway with drugs.” said Professor Martin Welch.
We know that many people with CF live with long term lung infections caused by Pseudomonas aeruginosa and we desperately need better, more effective ways to treat them. We’re delighted that our investment in this area of research has generated such important results, and brought our goal of developing more effective treatments for CF infections one step closer
Dr Lucy Allen, Director of Research and Healthcare Data at Cystic Fibrosis Trust
Read more about the results of this research in the Nature Communications paper, and read the story on the University of Cambridge website.
More details about what the researchers found
Dr Meng Wang, a post-doctoral research fellow in Prof Welch’s lab, took on the challenge of finding out more about the enzymes that break down fatty acids in P. aeruginosa and how to stop them working. It was a collaborative effort with researchers from different departments at the University of Cambridge, and labs from Exeter in the UK, Finland and Germany.
Narrowing down the search
The first challenge to overcome was to work out which enzymes were breaking down fatty acids in the strains of P. aeruginosa growing in the lungs of people with CF. There are over 20 enzymes that potentially carry out this job in the cell, and a major obstacle has been in establishing which of these are actually involved. Dr Wang found that only two of the enzymes are used by the bacteria to breakdown fatty acids.
How to prevent the enzymes working
Researchers used advanced structural and computational analyses to identify two chemicals that reduce the activity of these enzymes. They showed that the chemicals could work using computer models of the enzyme, and also by testing their ability to block enzyme activity in the lab.
The next steps will be to see if this approach could be used to develop potential new medicines to treat Pseudomonas aeruginosa infections.
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