A systematic assessment of genotoxicity on pivaloylacylation-7ADCA-a wide existing antibiotic impurity.

The safety of antibiotics has been becoming an important worldwide concern. As an inevitable and widespread existing impurity of β-lactam antibiotics, pivaloylacylation-7ADCA may has potential impact on drug safety. However, due to the restriction on traditional drug production technique, purified pivaloylacylation-7ADCA cannot be acquired and thus the toxicity of pivaloylacylation-7ADCA remains completely unknown. In this study, we firstly assessed the genotoxicity of newly purified pivaloylacylation-7ADCA. A series of well-designed experiments, including bacterial reverse mutation assay (Ames assay), mouse lymphoma assay (TK gene mutation test), chromosomal aberration assay, in vivo mouse micronucleus test and single cell gel electrophoresis assay (comet assay), were performed in genotoxicity assessment of pivaloylacylation-7ADCA at three different genetic endpoints, i.e. gene mutation, chromosome aberration or breakage, and DNA strand breaks. No genotoxicity were observed at all tested genetic endpoints, suggesting that pivaloylacylation-7ADCA has no mutagenic effect. To our knowledge, this is the first systematic assessment on the toxicity of newly synthesized pivaloylacylation-7ADCA, which should be an important part of the drug safety evaluation of β-lactam antibiotics. Moreover, our study is expected to serve as a reference for the genotoxicity assessment of other antibiotic impurities, by using purified impurity as test sample and by combining a group of well-designed genotoxic assays with different species, major genetic endpoints and in vivo/vitro tests.