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Identifying antibiotics that are less toxic to the ear

We funded a consortium of researchers from universities and industry to identify antibiotics, which are less toxic to the ear, but that are still effective in fighting life-threatening bacterial infections. The results have now been published in the journal Scientific Reports. Our Translational Research Manager, Dr Carina Santos, tells us more about their work.

Aminoglycoside antibiotics, such as gentamicin, are a type of antibiotic which are very effective in treating life-threatening bacterial infections, but that have serious side effects. These antibiotics are highly toxic to the kidney and ear. Although the damage to the kidney is reversible, the ear suffers permanent damage, which leads to hearing loss.

Their high toxicity was the reason why, in the 1970’s, aminoglycoside antibiotics were mostly replaced by other antibiotics that were less toxic but just as effective in fighting infections. Despite their toxicity, aminoglycoside antibiotics are still routinely used in neonatology to help the underdeveloped immune system of premature babies to fight serious bacterial infections, like sepsis. Due to their low cost, they are still used in some developing countries as first line treatments. In recent years, a rapid spread of bacteria, which are resistant to the currently used antibiotics, has made it urgent to identify antibiotics that are efficient in fighting life-threatening bacterial infections, but that are also safer and do not lead to debilitating side effects.

In 2014, Action on Hearing Loss awarded a Translational Research Grant (TRIH grant) to a group of academic researchers from universities in Germany and Spain and researchers from the company ACIES BIO Ltd, in Slovenia. The funded work aimed to identify aminoglycoside compounds, which are antibacterial without being toxic for the ear. The outcome of the project has now been published in the journal Scientific Reports and shows promising results for the development of safer antibiotics, in the future.

Are different types of aminoglycoside antibiotics equally toxic to the ear?

The researchers tested different types of aminoglycoside antibiotics that are currently used to treat people, despite their known toxicity to the ear, these were: gentamycin, neomycin and paromomycin. They compared their toxicity to gentamycin C1a (GMC1a), isolated from the gentamycin antibiotic mix used in the clinic, and apramycin, an antibiotic currently used in veterinary medicine.

The results showed that both GMC1a and apramycin have a strong antibacterial activity against multi-drug resistant bacteria and therefore could be used to treat life-threatening bacterial infections. Although all antibiotics were toxic with increasing doses, GMC1a and apramycin showed the lowest toxicity to the cochlea, compared with the others that are regularly used in the clinic.

When the antibiotics currently used in the clinic were administered to guinea pigs at a low dose, the researchers did not observe a reduction in the number of hair cells in the cochlea. Although, at first sight, this could mean that no damage had been caused to the cochlea, they soon found out that this was not the case. In fact, even with the low dose of the antibiotics there was a reduction in the number of connections between the hair cells in the cochlea and the neuronal fibres that connect the inner ear to the auditory nerve, which takes the sound information to the brain.

This is known as “hidden hearing loss” and cannot be detected in the hearing tests typically used in the clinic to assess hearing loss. These results suggest that the loss of connections between the ear and the brain, which compromises the communication between the two, is the first consequence of the toxicity caused by aminoglycoside antibiotics. This seems to take place before any decrease in the number of hair cells is observed. Interestingly, researchers could not detect “hidden hearing loss” in the animals that were treated with the low dose of GMC1a and Apramycin, suggesting that these antibiotics are safer and not so damaging to the cochlea, when compared to the ones currently used the clinic, like neomycin and gentamycin.

Why this study is important

The identification of Apramycin and GM C1a as safer aminoglycoside antibiotics that are less toxic to the ear but still effective against life-threatening bacterial infection can serve as the basis to develop new antibiotics.

3D illustration of Mycobacterium tuberculosis bacteria in the lungs

The crucial role of antibiotics in treating fatal bacterial infectious is unquestionable. The rapid increase and spread in the number of bacteria that are resistant to the currently used antibiotics makes it harder to treat serious infections, such as pneumonia and tuberculosis. It is urgent to find viable alternatives, which preferentially do not cause debilitating side effects, such as permanent hearing loss. This work contributes to increasing our knowledge about those safer alternatives. Although researchers all over the world are developing medicines to prevent the hearing loss caused by aminoglycoside antibiotics, the best alternative would be to have antibiotics which do not cause hearing loss in the first place.

Further information

This research was published in the journal Scientific Reports.

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