Dr Martin Welch and his co-investigators have designed a comprehensive set of integrated work programmes to help answer a key question in CF research: why does the bacteria Pseudomonas aeruginosa thrive so well in the airways of people with cystic fibrosis? Understanding the answers to this question will help to design of new, more effective antibiotics.
Background and introduction
As you read this, there are hundreds of chemical reactions taking place in your body. These chemical reactions are generally organised into sequences or ‘pathways’. In the same way, there are lots of chemical reactions taking place in bacteria, to allow them to grow and survive.
Antibiotics work by blocking one of the chemical reactions in these pathways, specifically those that allow the bacteria to grow and survive. Current antibiotics are designed to work against a small proportion of these chemical reactions. An emerging area of research is looking to be smarter about choosing which chemical reactions researchers should design drugs to block.
Like taking different routes to work depending on the weather, bacteria can adapt to the local environment (CF airways or non-CF airways, for example) by choosing which chemical pathway to use. These changes can be seen in which nutrients the bacteria require, the constant change in how they use these nutrients to grow and survive, and how their genes are altered to drive these changes.
In this SRC, researchers will use a comprehensive and complementary set of approaches to investigate this interplay of changing nutritional requirements, changing biochemistry and adaptive genetics to understand how and why Pseudomonas colonises the airways of people with cystic fibrosis. Armed with this new knowledge, they will determine if there are new ways to tackle these infections.
Aims of the project
The SRC is divided into six aims, each addressing a specific question.
1. How does the diet of Pseudomonas change as it evolves to live in the CF airways, and how does it change genetically to achieve this?
The researchers are interested to know which chemical pathways are preferred by Pseudomonas as it adapts to growing in the CF airways. One way to measure this is to look at what its food requirements are.
Pseudomonas grows much slower in the lungs of someone with CF compared with how it grows in the environment. The speed of growth is controlled by the genetic makeup of Pseudomonas. Knowing how and why it slows down in the lungs could provide a new target for antibiotic drug development.
2. What biochemistry do the bugs use in the adapted state, and what food do they need to do this?
The researchers want to study how Pseudomonas strains grow and survive once they’ve adapted to the CF airways. What are the possible nutrients that they could eat, how do they use them (ie which chemical pathways are required), and what are the differences in the food and pathways employed by different strains?
3. How does the genetic makeup of Pseudomonas affect how it settles in the CF airways?
The way that Pseudomonas behaves so that it can survive in the CF airways is a finely tuned response that is ultimately controlled by its ‘gene expression profile’. For example, different genes may be ‘active’ depending on whether it’s an early or late-stage infection. Work by one team member on the SRC has shown that there is a core set of genes that are actively used by Pseudomonas only in the CF lung. The aim is to understand the function of this core ‘CF set’ of genes, and to investigate which of them could be suitable targets for new antibiotics.
4. Could stopping fatty acid breakdown be a way to treat Pseudomonas infection?
Pseudomonas can break down a specific group of chemicals present on the surface of the lungs, known as fatty acids, and then use them as nutrients to grow and survive. Work is in progress to develop drugs that prevent Pseudomonas from breaking down one particular type of fatty acid, and one of the aims of the SRC is to extend this work by understanding how Pseudomonas uses other fatty acids in the CF airways.
5. How does Pseudomonas react to the presence of other infections in the CF airways?
How Pseudomonas grows in the airways is also influenced by the presence of other bacterial, fungal and viral infections. The team is aiming is to understand more about its survival tactics in such competitive environments, by looking at changes in which Pseudomonas genes are active in different situations.
6. How does Pseudomonas use the food it is given?
As well as measuring what nutrients Pseudomonas eats, and how differences in the stage of the infection and strain of the bacteria influence this, the researchers will also use sensitive tracers called isotopes to track exactly what happens to the food as it gets used by Pseudomonas.
Principal investigator: Dr Martin Welch, University of Cambridge
- Professor Helle Krogh Johansen, Technical University of Denmark, Lyngby
- Professor Soren Molin, Technical University of Denmark, Lyngby
- Professor Susanne Haussler, The Helmholz Centre for Infection Research, Braunschweig, Germany
- Professor Dieter Jahn, Braunschweig University of Technology, Germany
- Professor Marvin Whiteley, Georgia Institute of Technology, Atlanta, USA
- Dr Pablo Ivan Nikel, Technical University of Denmark, Lyngby