Exploiting the weak spots in M abscessus to design new antibiotics

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Trust-funded researchers at the University of Cambridge recently published a report on their progress in designing new antibiotics against the cystic fibrosis (CF) lung infection Mycobacterium abscessus (part of the NTM group of bacteria). These antibiotics are being designed to exploit a new weak spot in the bacteria. Here, we explain why new weak spots are important and what has been achieved so far.

Mycobacterium abscessus (M. abscessus) is a bacteria that causes an aggressive lung infection in people with cystic fibrosis. It is extremely difficult to treat and can take over a year of strong antibiotic treatments to clear, where these can have damaging and unpleasant side effects. Some strains of M. abscessus are also becoming resistant to the current antibiotics that are prescribed. More effective treatments are urgently required. There have been no new antibiotics developed for over 30 years, so innovative thinking is required for the development of new ones.

Acts of bacterial-protein sabotage

Antibiotics work by sabotaging the production of proteins within the bacteria. As the production of proteins is a complex process, there are a number of possible stages where the sabotage can take place.

Current antibiotics work by interrupting the early stages of protein production; however, bacteria develop ways of becoming resistant to their effects. Researchers within the UK CF Innovation Hub at the University of Cambridge have been targeting an alternative weak spot – in the later stages of protein production – as a new way for designing antibiotics against the CF infection-causing bacteria M. abscessus.

Proteins are made by assembling a specific combination of 20 building blocks (called amino acids) in a specific order. Sometimes the assembly machinery misreads which building block comes next and inserts the wrong one. These errors are corrected in a quality control step of protein production, where a ‘quality control’ protein prevents any damaging misreading of the assembly instructions. Without the quality control, these errors could change the shape and properties of proteins entirely and mean they could no longer function.

Researchers working in the Floto, Abell and Blundell labs within the Innovation Hub have started designing a new antibiotic to target a ‘quality control’ protein within M. abscessus, using a technique called ‘fragment-based drug design’ (FBDD). They believe that sabotaging this protein will halt the growth and survival of M. abscessus.

Fragment-based drug design

Scientists working within the Innovation Hub pioneered the use of FBDD, which has resulted in new licenced treatments for cancer. They are now using it to design antibiotics to treat CF-related lung infections. It is a process designed to be quicker and more efficient than traditional methods of drug design.

In June they published some results of their research to date, showing that they are making good progress in designing new antibiotics against M. abscessus infection. Their results demonstrate for the first time that FBDD is a technique that can be used to design new antibiotics.

Designing a new drug using FBDD

Designing a drug using FBDD is a methodical process. In a recent article on antimicrobial resistance, we described FBDD in terms of designing a bespoke shoe. Here we go into more detail, outlining the FBDD drug design process in five steps, and explain the progress that the researchers within the Innovation Hub have made so far, using FBDD to target their ‘quality control’ protein in M. abscessus.

1. Understand the shape of the protein you want to target.

To design a new drug, researchers need to start by understanding the protein they would like to target.

M. abscessus drug design: A ‘quality control’ protein within M. abscessus has been identified as the protein to target and this has been extensively studied by the Innovation Hub team.

2. Do the corners first (like a jigsaw).

 Drugs are designed to fit a specific ‘pocket’ in a protein, where each corner of the pocket has a different shape and chemical properties.

M. abscessus drug design: The researchers have searched through a library of fragments of molecules for those with matching shapes and chemical properties to the drug pocket. They used a range of lab techniques to analyse how well the fragments match, and optimised the chemical properties of their fragments to achieve a better fit.

3. Join the corners together to make a single molecule.

Once researchers are happy with how well the separate fragments fit the different corners of the target ‘pocket’, the next step is to chemically join the fragments together to make a potential new drug.

M. abscessus drug design: The Innovation Hub team prepared a number of different potential drugs, made from joining fragments together.

4. Fine-tuning of the potential drug.

After the fragments have been joined together, the researchers do another round of fine-tuning of the chemical structure. They carefully adjust the chemical properties of the potential drug to achieve as good a fit as possible within the protein.

M. abscessus drug design: A further set of checks have been performed, using similar analysis techniques to those used in step 2 when the fit of the individual fragments were examined.

5. Testing whether the potential drug has an effect

This stage of the FBDD process is different depending on what the drug is designed to do, for example, whether it is an anti-cancer drug or a new antibiotic.

M. abscessus drug design. Firstly, the Innovation Hub researchers showed that their potential drugs prevented M. abscessus from growing in a culture dish in the lab. At the same time they showed that the potential drugs are only interacting with the ‘quality control’ protein target, and not any other M. abscessus proteins.

They also showed that their potential drugs can get into human blood cells infected with M. abscessus, and stop the bacteria from growing. This is one of the most important steps so far as it is an early sign of how easy it may be to get the potential drug to where it needs to be in people with cystic fibrosis.

The researchers have shown as a ‘proof of principle’ that this approach could work. The next steps will be to carry on optimising the properties of the potential drugs to see if they can reduce the amount needed to kill M. abscessus and continue testing in more complex lab models of M. abscessus infection.

This article was based on the research described in two research papers from the Innovation Hub scientists: Whitehouse et al 2019 and Thomas et al 2020 .

Designing new antibiotics to fight infections like M. abscessus is an important part of our work in tackling antimicrobrial resistance. You can help fund this vital work by signing up to our latest challenge 'Ride for Research' this October, or make a contribution by donating today.

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