Environmentally Friendly Quinolones Design for a Two-Way Choice between Biotoxicity and Genotoxicity through Double-Activity 3D-QSAR Model Coupled with the Variation Weighting Method.

Peixuan Sun,Luze Yang,Wenjin Zhao,Yuanyuan Zhao,Zhixing Ren

doi:10.3390/ijerph17249398

Abstract

Quinolone (QN) antibiotics are widely used, which lead to their accumulation in soil and toxic effects on ryegrass in pasture. In this study, we employed ryegrass as the research object and selected the total scores of 29 QN molecules docked with two resistant enzyme structures, superoxide dismutase (SOD, PDB ID: 1B06) and proline (Pro, PPEP-2, PDB ID: 6FPC), as dependent variables. The structural parameters of QNs were used as independent variables to construct a QN double-activity 3D-QSAR model for determining the biotoxicity on ryegrass by employing the variation weighting method. This model was constructed to determine modification sites and groups for designing QNs molecules. According to the 3D contour map of the model, by considering enrofloxacin (ENR) and sparfloxacin (SPA) as examples, 23 QN derivatives with low biotoxicity were designed, respectively. The functional properties and environmental friendliness of the QN derivatives were predicted through a two-way selection between biotoxicity and genotoxicity before and after modification; four environmentally friendly derivatives with low biotoxicity and high genotoxicity were screened out. Mixed toxicity index and molecular dynamics methods were used to verify the combined toxicity mechanism of QNs on ryegrass before and after modification. By simulating the combined pollution of ENR and its derivatives in different soils (farmland, garden, and woodland), the types of combined toxicity were determined as partial additive and synergistic. Binding energies were calculated using molecular dynamics. The designed QN derivatives with low biotoxicity, high genotoxicity, and environmental friendliness can highly reduce the combined toxicity on ryegrass and can be used as theoretic reserves to replace QN antibiotics.

Highlights

Antibiotics are a class of active drug compounds widely used in human and veterinary medicines, aquaculture, and agriculture [1], and which are often employed to prevent or treat microbial infections [2]
Because this study explored the toxicity changes in QN molecules before and after modification, the horizontal comparison principle was adopted to compare the changes in combined toxicity of different derivatives and ENR based on the original ENR molecule, and the combined toxicity of multiple mixtures was considered
In the garden and woodland soil, the MTI values of QNs were >1, indicating that the combined toxicity of ENR and its derivatives was synergistic, and the MTI values of all the 22 simulated combinations were higher than the biotoxicity values of ENR

Summary

Introduction

Antibiotics are a class of active drug compounds widely used in human and veterinary medicines, aquaculture, and agriculture [1], and which are often employed to prevent or treat microbial infections [2]. Quinolone (QN) antibiotics have emerged as one of the most commonly used antibiotics worldwide because of their wide antibacterial spectrum, high efficiency, and strong bactericidal effect [3,4]. Compared with other types of antibiotics, QNs are characterized by their long biological half-life and difficult degradation [5]. Studies have shown that 60–90% of veterinary or. Res. Public Health 2020, 17, 9398; doi:10.3390/ijerph17249398 www.mdpi.com/journal/ijerph

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