A new parameter for quantitatively characterizing antibiotic hormesis: QSAR construction and joint toxic action judgment

Antibiotics usually induce the hormetic effects on bacteria, featured by low-dose stimulation and high-dose inhibition, which challenges the central belief in toxicity assessment and environmental risk assessment of antibiotics. However, there are currently no ideal parameters to quantitatively characterize hormesis. In this study, an effective area in hormesis (A_H) was developed to quantify the biphasic dose-responses of single antibiotics (sulfonamides (SAs), sulfonamides potentiators (SAPs), and tetracyclines (TCs)) and binary mixtures (SAs-SAPs, SAs-TCs, and SAs-SAs) to the bioluminescence of Aliivibrio fischeri. Using E_bind (the lowest interaction energy between antibiotic and target protein) and K_ow (octanol-water partition coefficient) as the structural descriptors, the reliable quantitative structure-activity relationship (QSAR) models were constructed for the A_H values of test antibiotics and mixtures. Furthermore, a novel method based on A_H was established to judge the joint toxic actions of binary antibiotics, which mainly exhibited synergism. The results also indicated that SAPs (or TCs) contributed more than SAs in the hormetic effects of antibiotic mixtures. This study proposes a new quantitative parameter for characterizing and predicting antibiotic hormesis, and considers hormesis as an integrated whole to reveal the combined effects of antibiotics, which will promote the development of risk evaluation for antibiotics and their mixtures.

Environmental Implication

Antibiotics usually induce hormetic phenomena in bacteria, characterized by low-dose stimulation and high-dose inhibition, which may influence the microbial community and thus disrupt the balance of the entire ecosystem. A new parameter, i.e., the effective area, was established to quantity and predict the hormetic effects of typical antibiotics and their mixtures at environmentally relevant concentration, which could also judge the joint toxic actions of antibiotics when triggering hormesis based on the co-existence of antibiotics in environmental media. This study will promote the application of hormesis in the toxicity test and environmental risk assessment of antibiotics and their mixtures.