One of the biggest public health problems in the world is resistance to antibiotics. In Europe, around 33,000 people die each year from infections resistant to antibiotics, such as those caused by Acinetobacter baumannii or Pseudomonas aeruginosa, both declared priority targets by the World Health Organization (WHO).
Developing new antibiotics capable of dealing with these dangerous microorganisms is a critical issue that the scientific community is facing. An interdisciplinary team of researchers from the Institute of Biology and Molecular Genetics (IBGM) (a mixed center of the University of Valladolid and the CSIC), the University of Tübingen in Germany), Slovenian biotechnologists, and the University Hospital Marqués de Valdecilla of Santander verified the potential of gentamicin C1a and apramycin as new antibiotics.
In the paper, published in Scientific Reports, the authors studied a large sample of aminoglycoside antibiotics (AGs), very effective antibacterial agents but with significant side effects, as they cause serious damage especially in the kidney and the ear.
“Although a possible renal failure is a very serious concern for doctors, nephrotoxicity is often reversible. On the contrary, ototoxicity is irreversible: the ciliated cells of the inner ear, damaged by these antibiotics, do not recover or are replaced by new ones, with the consequent loss of hearing, possible problems of vertigo, loss of balance, etcetera,” explains María Beatriz Durán, researcher at IBGM.
For this reason, in the 70s, aminoglycoside antibiotics were replaced by more safe antibiotics, fluoroquinolones. However, with the increase in the number of bacterial infections resistant to fluoroquinolones and the shortage of new antibiotics, the AGs “are part of the last defense against this type of very dangerous infections, causing pneumonia, peritonitis or sepsis,” Durán adds.
“These antibiotics have very favorable pharmacokinetic properties for their use and administration, for example, their solubility in water, and they are effective against a broad spectrum of pathogens. Their production is low cost; that is why they are used so frequently in developing countries, which consequently have high rates of hearing problems,” she says.
In search of new antibiotics
The team of researchers, specialized in the study of the inner ear, went to work in the search for aminoglycoside antibiotics capable of eliminating these pathogens but with reduced toxicity.
As Durán said, they selected those most effective to kill multiresistant bacteria at as-low-as-possible concentrations, and simultaneously analyzed which were not toxic to two mouse cell lines that represent cell types similar to the hair cells of the ear, which are the ones damaged after the use of aminoglycoside antibiotics and which loss leads to hearing problems.
Those that were non-toxic or low-toxic were tested on tissue obtained from mice’s cochlea —the organ of the inner ear where the sense of hearing resides. Finally, they selected some antibiotics that proved to be effective against the panel of pathogens and showed low toxicity on the hair cells, to be tested in vivo in guinea pigs. The team observed that, at concentrations of AGs in which the auditory capacity parameters were good, there was another type of damage.
“The hair cells were there, but what was damaged was the communication of the inner hair cells, with the auditory neurons, which are the ones that carry the auditory signal from the cochlea to the brain,” says the scientist. This fact, he emphasizes, must be taken into account when evaluating the possible ototoxicity of substances that are administered to patients in hospitals, such as aminoglycoside antibiotics.
Part of a large international study
From the sample of antibiotics studied, they identified gentamicin C1a and apramycin as the two most promising to bring to the clinic. However, the intention of the group is to carry out future studies of nephrotoxicity with these antibiotics. This work is part of a large international study of aminoglycoside antibiotics.
“A great collaboration has been established between laboratories of different expertise. The work is the result of the interest of these groups to join their lines of work, in an effort to take their studies from a basic research plan to a therapeutic application, to reach a point where the patient benefits directly from the research. Of course, this is not a short-term goal, but it is very important that there are collaborations of this kind, multidisciplinary, where different groups work in the same direction and interact, favoring the work of their collaborators,” concludes the researcher.