This is a Discovery Research Grant awarded to Professor Alan Cheng at Stanford University, USA, in 2022. We are funding this grant in partnership with the Cystic Fibrosis Trust.
Background
Aminoglycosides are a class of antibiotics which are used to treat a broad range of bacterial infections. However, they can also cause permanent hearing loss (ototoxicity) as a side-effect. Around 1 in 5 people treated with aminoglycosides will develop hearing loss as a result. This number increases in people who require repeated treatment or if they have genetic mutations that put them at higher risk.
Aminoglycosides are commonly prescribed worldwide despite their ototoxicity because they are cheap, effective, and have low rates of antibiotic resistance. In the UK, aminoglycosides are used to protect premature babies from infection as their immune system is not fully developed. They are also used to treat people with cystic fibrosis who develop persistent lung infections that only respond to aminoglycoside treatment – they are therefore particularly at risk of developing hearing loss. Aminoglycosides are also used widely in low- and middle-income countries where they cause significant levels of hearing loss. Despite this, there are no treatments available to protect people’s hearing when they take these antibiotics.
Aminoglycosides cause hearing loss by getting into the sound-sensing hair cells of the inner ear and irreversibly damaging them. They are thought to damage hair cells in the same way that they kill bacteria. Therefore, the best way to protect someone’s hearing from these drugs may be to prevent them getting into hair cells in the first place.
Aims
Researchers at Stanford University, led by Dr Alan Cheng, have been developing aminoglycoside antibiotics that are less damaging to hearing but still effective at treating infection. They modify the chemical structure of existing aminoglycoside antibiotics to try to prevent them from entering hair cells without interfering with their antibacterial activity. So far, they have generated over 30 new aminoglycosides, and they have taken 3 forward for further development (these are called ‘lead compounds’).
In this project, the researchers will test their lead compounds on hair cells grown in the lab to measure their ototoxicity compared to the original aminoglycoside. They will also develop chemically modified versions of two other aminoglycosides to generate additional compounds to be tested. The compounds will also be tested to ensure they retain their antibacterial activity.
The most promising compounds will be tested in an animal model of bacterial wound infection to assess their ability to clear the infection without causing hearing loss.
Benefit
If this research is successful, it will generate new, less ototoxic aminoglycosides that can be developed further towards clinical testing in people. Such aminoglycosides would allow people suffering from serious bacterial infections, and those having to be frequently treated for infection, such as cystic fibrosis patients, to benefit from effective antibiotics without losing their hearing.