Redesigning aminoglycoside antibiotics to prevent hearing loss side effects: a research explainer

Feature - 09/11/2022

Aminoglycosides are a group of antibiotic medicines such as tobramycin, amikacin and gentamycin. They are very effective at treating CF lung infections such as Pseudomonas aeruginosa and NTM. However, a side effect of long term use of aminoglycosides is that they can cause permanent hearing loss. In June we announced co-funding with RNID of a research grant to redesign aminoglycosides to prevent hearing loss. The research is being led by Dr Cheng and colleagues at the prestigious Stanford University in America. Here we explain their research in more detail.

Image of an ear Everyone with CF has a different experience of the condition and so it is difficult to say how many people with CF are affected by hearing loss side effects of aminoglycoside antibiotics. Researchers estimate it may be as high as 50% of adults with the condition. It is something RNID and Cystic Fibrosis Trust are working to stop.

How do aminoglycosides cause hearing loss?

Aminoglycoside medicines cause hearing loss when they enter very thin and wavy ‘hair’ cells in part of the ear known as the cochlea. There are thousands of hair cells within the cochlea. When aminoglycosides enter a hair cell, it causes it to die.

The cochlea is the area in the ear where sound waves are converted into electrical nerve signals, these tell our brain that we can hear things. The cochlea is in part of the ear known as the inner ear. You can find out more about how the ear works on the RNID website.

Dr Cheng and colleagues aim to change the shape and design of the medicines to prevent them from entering the hair cells in the ear, and so prevent the toxicity and hearing loss. There are many different stages in the research programme to redesign these antibiotics. We’ve summarized them in four steps below:

Four steps to redesign aminoglycosides

1. Design a new ‘prototype’ medicine

No, we’re not talking the latest car model being talked about on Top Gear! Here we’re talking about what Dr Cheng’s new designs of a toxicity-free aminoglycoside antibiotic could look like. The researchers are focusing on new versions of the medicines gentamicin, tobramycin and sisomicin. Typically they will make several slightly different versions of each of these medicines to increase the chances of a successful prototype.

2. Devise a chemical ‘recipe’ to make the protype medicine

Changing the chemical structure of medicines, needs to be done in several steps, completing each step before moving on to the next. A bit like a completing each stage of a recipe. The researchers have worked out the best chemical recipe for modifying aminoglycosides. The newly designed chemicals are checked to ensure that the recipe has made what they want to make.

3. Test, test and test again

The first step is to ensure that the redesigned medicines still work as antibiotics. In other words, do they still kill the CF bacterial infections that they’re supposed to treat, at the same concentrations as before. The second test is to look at the effect of medicines on hearing loss. Firstly, Dr Cheng and colleagues will look at whether the new prototypes cause the hair cells in rat cochlea to die in the lab. As they know exactly where aminoglycoside medicines enter the hair cells, they will check what happens at this entry point too!

4. Refine and repeat!

Depending on the results of the tests in the lab, the new medicine prototypes will either be refined further and tested again (repeating steps 1 to 3 above), or more complex testing will be carried out. The further tests will be designed to mimic how the medicines are likely to be used, for example, applying the medicines multiple times to mimic taking a course of antibiotics.

At the end of the three-year research study, the researchers aim to have at least three of the prototype medicines that they can move to the ‘preclinical’ stage of developing new medicines. This means that people with CF in the future will be able to take medicines to treat their lung infections, without the risk of causing hearing loss.

If you are concerned about developing hearing loss as a result of aminoglycosides antibiotics, please raise any questions or concerns with your CF team.

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