Chemical Modifications Reduce Auditory Cell Damage Induced by Aminoglycoside Antibiotics.

Although aminoglycoside antibiotics are effective against Gram-negative infections, these drugs often cause irreversible hearing damage. Binding to the decoding site of the eukaryotic ribosomes appears to result in ototoxicity, but there is evidence that other effects are involved. Here, we show how chemical modifications of apramycin and geneticin, considered among the least and most toxic aminoglycosides, respectively, reduce auditory cell damage. Using molecular dynamics simulations, we studied how modified aminoglycosides influence the essential freedom of movement of the decoding site of the ribosome, the region targeted by aminoglycosides. By determining the ratio of a protein translated in mitochondria to that of a protein translated in the cytoplasm, we showed that aminoglycosides can paradoxically elevate rather than reduce protein levels. We showed that certain aminoglycosides induce rapid plasma membrane permeabilization and that this nonribosomal effect can also be reduced through chemical modifications. The results presented suggest a new paradigm for the development of safer aminoglycoside antibiotics.

Predicting the long-term toxicity of five-antibiotic mixtures to Vibrio qinghaiensis sp. Q67.

Concentration addition (CA) is commonly used as a standard additive reference model to predict the short-term toxicity for most chemical mixtures. Whether CA can predict the long-term toxicity of antibiotic mixtures was investigated. The long-term toxicity of five antibiotics including apramycin sulfate, paromomycin sulfate, tetracycline hydrochloride, chloramphenicol and streptomycin sulfate and their mixtures to a photo bacterium Q67 were detected by the long-term toxicity microplate analysis procedure. Seven five-antibiotic mixtures with various concentration ratios and concentration levels were designed by employing uniform design ray method. The long-term mixture toxicity was predicted by CA based on the toxicity data of single antibiotics. The results showed that Weibull or Logit function fit well with the long-term toxicity data of all the components and their mixtures (R>0.98 and RMSE<0.07). According the toxicity index, the negative logarithm of mean effect concentration, the long-term toxicity of the five antibiotics differs greatly and is higher than their short-term toxicity. The predicted values by CA model conformed to the experimental values of mixtures, which implies CA can predict reliable results for the long-term toxicity of antibiotic mixtures.

Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin.

Aminoglycosides are potent antibacterials, but therapy is compromised by substantial toxicity causing, in particular, irreversible hearing loss. Aminoglycoside ototoxicity occurs both in a sporadic dose-dependent and in a genetically predisposed fashion. We recently have developed a mechanistic concept that postulates a key role for the mitochondrial ribosome (mitoribosome) in aminoglycoside ototoxicity. We now report on the surprising finding that apramycin, a structurally unique aminoglycoside licensed for veterinary use, shows little activity toward eukaryotic ribosomes, including hybrid ribosomes which were genetically engineered to carry the mitoribosomal aminoglycoside-susceptibility A1555G allele. In ex vivo cultures of cochlear explants and in the in vivo guinea pig model of chronic ototoxicity, apramycin causes only little hair cell damage and hearing loss but it is a potent antibacterial with good activity against a range of clinical pathogens, including multidrug-resistant Mycobacterium tuberculosis. These data provide proof of concept that antibacterial activity can be dissected from aminoglycoside ototoxicity. Together with 3D structures of apramycin-ribosome complexes at 3.5-Å resolution, our results provide a conceptual framework for further development of less toxic aminoglycosides by hypothesis-driven chemical synthesis.

[Subchronic toxicity of apramycin in pigs]. / Subkhronichna toksichnost na apramitsina pri praseta.

Use was made of four groups of six pigs each, weighing 40 to 50 kg to follow up the toxicity of Pharmachim's apramycin in the form of water-soluble powder of apramycin sulfate, given at the rate of (nil), 300, 500, and 1,000 mg per liter of drinking water in the course of 35 days. It was found that such treatment did not lead to changes in the general status of the animals. On the contrary, apramycin sulfate stimulated growth and improved feed conversion. In concentrations of up to 300 mg/l the preparation did not produce an essential effect on the clinico-laboratory indices, and did not lead to toxic alterations of the viscera. In concentrations of 500 and 1,000 mg/l and extending the period to more than 15 days an occasional drop of the percent of lobular neutrophilic leukocytes and rise of the percent of lymphocytes in the blood might occur. This could lead to dystrophic processes in the liver and to negligible changes of the same character in both the kidneys and the heart.

[Chronic 90-day toxicity of apramycin in chickens]. / Prouchvane vurkhu khronichnata 90-dnevna toksichnost na apramitsina pri pileta.

Investigations were carried out on 72 2-day-old broilers, divided into four groups (one control group--27 broilers and 3 experimental groups--15 broilers in each), treated with apramycin sulphate (AS), which was added to the food in concentration 0, 330, 1000 and 1600 mg/kg (corresponding to 0, 50, 150 and 250 mg/kg m.), in the course of 90 days. It was established that dose of 50 mg/kg m. AS does not causes toxic activities. With doses of 50, 150 and 250 mg/kg m. AS causes reduction of the degree of the pseudo-eosinophilic cells and increase of the percentage of leucocytes--in range similar to the physiological variations, contributes to stimulate the growth and the feed conversion. With doses of 150 and 250 mg/kg m. AS causes reduction of the content of haemoglobin and reduction of the number of erythrocytes; causes dystrophic changes in the internal organs.