An international research team led by scientists at the University of Zurich and ETH Zurich has succeeded in improving a class of early-generation antibiotics: they have been able to suppress their once serious side effects.
Antibiotic is more selective
"We have now modified the mode of action of antibiotics of this group so that they can distinguish between human and pathogenic ribosomes far better," explains Böttger. Based on a number of compounds that were synthesised at the ETH, his research group identified the 4’-hydroxyl position in the molecular structure of the aminoglycosides as the point that needed to be adapted in order to prevent these from wrongly latching onto the human ribosome. Both working groups then developed a model for how the structure should be changed at this point.
An experimental test system developed by Böttger’s group proved to be crucial for the success. This enabled the relevant compounds to be identified from the hundreds of compounds synthesised by Vasella’s group. "The results are a good example of how fruitful a cooperation between chemists and biologists at the University of Zurich and ETH Zurich can be," says Vasella. Other leading international research groups were also involved in the project, such as that of structural biologist Venkatraman Ramakrishnan at the MRC Laboratory of Molecular Biology in Cambridge, United Kingdom, who was awarded the Noble Prize for Chemistry in 2009 for his research into ribosomes.
The antibiotics that emerged in this project have a much more targeted effect than their predecessors: human auditory cells are now hardly damaged by the changed substance, while the antibiotic effect against pathogens is sustained, as shown in trials with mice infected with Staphylococcus aureus. Toxicological experiments shall follow as the next step, in which the effectiveness and the antibacterial potency are optimised, before the actual development of the medication can take place.
Medication from the 1940s
The antibiotic class of aminoglycosides was discovered in the 1940s and is very potent. Over the last few decades, however, it has somewhat receded into the background. This is not only to due the possible hearing damage and (reversible) damage to the kidneys that it may cause, but also the form of administration. When new antibiotics that could be easily swallowed in pill form came onto the market, these soon replaced the aminoglycosides that need to be intravenously injected or administered by infusion. Subsequently, further development on these stopped in the 1980s.
In the meantime, in the light of increasingly rampant resistance, experts now consider it necessary to again resort to this group of antibiotics. The World Health Organization has upgraded aminoglycosides into the group of drugs that are of crucial importance in fighting resistant and multi-resistant pathogens. Areas of application, for instance, are valvular inflammations or multi-resistant tuberculosis.
This is a slightly abbreviated version of an article by UZH News editor Thomas Müller, previously published on UZH News .
Literature reference
Perez-Fernandez D et al.: 4’-O-Ssubstitutions determine selectivity of aminoglycoside antibiotics. Nature Communications, Online publication 28 January 2014, doi: 10.1038/ncomms4112
