Aminoglycosides can cause deafness

(Image AdobeStock)
(Image AdobeStock)

Antibiotics belonging to the aminoglycoside class of substances damage hearing and, in the worst case, can lead to deafness. Microbiologist Erik Böttger has now deciphered the mechanism behind this. This lays the foundation for the development of antibiotics without this side effect.

Aminoglycosides are among the most widely used antibiotics. They are used in particular for severe and life-threatening infections. They also play an increasingly important role in the treatment of tuberculosis.

As a known side effect, however, aminoglycosides can damage hearing. Depending on how much and how long the antibiotic is administered, the consequences range from barely perceptible hearing loss in the upper frequency range to complete deafness. The problem is not negligible: In certain countries, such as Spain or China, up to 20 percent of deafness is due to antibiotic side effects.

Irreversible deafness

The side effects are even more serious for people who have a gene mutation associated with so-called mitochondrial deafness. Normally, the corresponding gene mutation leads sooner or later to hearing damage or hearing loss. In these people, aminoglycosides cause complete deafness almost immediately and irreversibly.

Erik Böttger, Director of the Institute of Medical Microbiology at the University of Zurich, is primarily concerned with ribosomes as targets for antibiotics. He came across mitochondrial deafness in his research because it is one of the few human diseases associated with the ribosome. The altered gene sequences are located in the mitochondrial ribosome, the energy producers in cells.

Not to be investigated with conventional methods

It is precisely at this site in the ribosome that the aminoglycosides dock. A connection between the genetically determined hearing loss and the antibiotic side effect could therefore be assumed, but could not yet be proven. This is because mitochondrial ribosomes cannot be studied using conventional genetic research methods.

The first step was therefore to create a suitable experimental model on which to study the mode of action. Böttger, whose laboratory is the only one in the world that can genetically modify ribosomes in this way, succeeded in introducing the mitochondrial gene sequence into a bacterium to which aminoglycosides dock and to which the genetic modification can also be found.

Mitochondria attacked instead of bacteria

Using this model, Böttger was able to demonstrate that the gene mutation impairs translation, i.e. the conversion of the gene code into proteins. This so-called "misreading" ultimately leads to the death of the hair cells in the auditory organ and thus to the hearing damage. Aminoglycosides, which dock onto the corresponding sites in the ribosome, also showed the same effect.

However, the gene mutation also causes the ribosomes in question to become much more susceptible to aminoglycosides. "This means that the antibiotic is no longer sufficiently selective in these patients and can only insufficiently differentiate between bacteria and human cells," Böttger explains. Instead of attacking the bacterium as desired, the antibiotic also acts on the human mitochondria.

In addition, the two effects reinforce each other: Aminoglycosides attack the genetically modified ribosomes more strongly than unmodified ones and also increase "misreading". This explains the severe reaction of people with mitochondrial deafness to aminoglycosides.

Aminoglycosides without side effects

The detailed findings on the mode of action of both the gene mutation and the aminoglycosides now allow Böttger to specifically develop an aminoglycoside that no longer exhibits this side effect. The results of this research so far are promising, Böttger said. However, it is likely to be some time before a ready-to-use antibiotic is developed, as extensive and complex series of tests are still pending.

Original contributions

Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity (PNAS Online).

Mitochondrial deafness alleles confer misreading of the genetic code (PNAS, vol. 105 no. 9 3244-3249).