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Research Blast on... Antimicrobial Resistance

Research into cystic fibrosis (CF) lung infections that show resistance to antimicrobial treatments is a top priority for the Cystic Fibrosis Trust. In this issue of Research Blast, we explore more about antimicrobial resistance in CF and how we’re working towards overcoming it

Q Why are infection-causing bugs in the CF lungs like characters in the film ‘Minions’?

A They’re always talking amongst themselves and plotting to cause trouble.

One of the reasons it can be hard to clear infections within the CF lung is because the bugs adapt to living there. As the bugs adapt, they regularly talk amongst themselves by passing chemical messages back and forth. This communication allows them to join forces and form a protective slime known as a biofilm. Biofilms can protect the bugs, both from the body’s natural defences and the effects of antimicrobial drugs, leading to antimicrobial resistance (AMR).

As part of our work to overcome AMR, we’re co-funding a PhD studentship in Professor Miguel Cámara’s lab at the University of Nottingham. The student, Simone Lucanto, is learning more about how the messages are carried between Pseudomonas aeruginosa bacteria, and whether intercepting the messages could make the bugs more susceptible to antibiotics. Simone is part of the first cohort of students from National Biofilm Innovation Centre’s prestigious BITE Doctoral Training Centre.

We recently explained how the bugs communicate to Candice, who is living with cystic fibrosis. “It’s like the characters in the film ‘Minions’!” she said. “Like the minions, all these bugs are making plots against me – and they’re both yellow!” Candice, your comparison was spot on, and thank you for letting us share it here!

Q How is the Innovation Hub’s approach to drug design like Cinderella’s slipper?

A It’s all about the perfect fit!

When the prince begins his search for the owner of the glass slipper in the renowned fairy tale, we know that Cinderella’s foot will be the perfect fit. Researchers within the Floto, Blundell and Abell labs as part of the Innovation Hub are also aiming for a perfect fit: of a drug that will perfectly fit into a specific part or ‘pocket’ of the target protein, to make new antibiotics for CF lung infections. When a drug fits into the protein, it will prevent a crucial, life-sustaining process within the bacteria.

Traditionally drug design uses an approach of high throughput screening (HTS) to make new drugs, testing thousands of ready-made molecules for how well they fit a particular part of the target protein. When they’ve narrowed down the search, researchers can then modify the molecule to make it a better fit. This can take a lot of time, with a high failure rate of the molecules that make it through the initial search.

Researchers within the Innovation Hub are using a pioneering technique called fragment-based drug design (FBDD): a process that is quicker and more efficient than using HTS to design new drugs. Fragments of molecules are chosen to specifically fit each part of the target pocket, and then are joined together to make a new drug. The researchers are making good progress in designing new antibiotics against the CF infection Mycobacterium abscessus (one of the ‘NTM’ group of infections). Like Cinderella’s perfectly-fitting slipper comparison, FBDD is like having a bespoke pair of shoes made, rather than trying on every shoe from every shop looking for a well-fitting pair.

Q Why is developing a new CF antibiotic like riding a winner at the Grand National?

A There are many fences to jump before you reach your goal.

After a molecule that fits the target protein has been found, there are still many more steps to complete before a drug can be licenced and used as a new antibiotic for CF lung infections. Completing each step has specific requirements that can be time consuming and costly to meet. Small biopharmaceutical and biotech companies are keen to develop new CF antibiotics but completing all of these steps can seem like high fences to overcome, and may prevent them from working in the area of cystic fibrosis.

The CF Syndicate in Antimicrobial Resistance, formed by the Trust and Medicines Discovery Catapult (MDC), has brought together a group of university, hospital and biopharmaceutical-based researchers working on antimicrobial therapies for CF, to help lower these ‘fences’ and make it easier to develop new antibiotics for cystic fibrosis.

One of these fences is facilitating easier access to samples from people with CF, including strains of bacteria and fungi from their lungs. Different individuals with CF will grow different sub-species, or ‘strains’, of bugs, and knowing which strain of bug causes the infection will make a difference to how it is treated. These strains are not standardly available to use in the lab, so access to clinical samples is needed to develop new antibiotics. It is usually very difficult and time consuming for companies to get access to these samples. The Syndicate are working on a way of making it much easier for drug developers to get access to high quality samples, improving and shortening the drug development process.

Ever wondered why it can be so tricky to fight some infections? We'll be talking more about how we’re working to beat AMR during our CF Live event in October. Send us an email at researchimpact@cysticfibrosis.org.uk if there is a question or topic on AMR you would like us to cover.