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Abstract：
Quorum sensing inhibitors (QSIs), as a kind of ideal antibiotic substitutes, have been recommended to be used in combination with traditional antibiotics in medical and aquaculture fields. Due to the co-existence of QSIs and antibiotics in environmental media, it is necessary to evaluate their joint risk. However, there is little information about the acute toxicity of mixtures for QSIs and antibiotics. In this study, 10 QSIs and 3 sulfonamides (SAs, as the representatives for traditional antibiotics) were selected as the test chemicals, and their acute toxic effects were determined using the bioluminescence of Aliivibrio fischeri (A. fischeri) as the endpoint. The results indicated that SAs and QSIs all induced S-shaped dose-responses in A. fischeri bioluminescence. Furthermore, SAs possessed greater acute toxicity than QSIs, and luciferase (Luc) might be the target protein of test chemicals. Based on the median effective concentration (EC50) for each test chemical, QSI-SA mixtures were designed according to equitoxic (EC50(QSI):EC50(SA) = 1:1) and non-equitoxic ratios (EC50(QSI):EC50(SA) = 1:10, 1:5, 1:0.2, and 1:0.1). It could be observed that with the increase of QSI proportion, the acute toxicity of QSI-SA mixtures enhanced while the corresponding TU values decreased. Furthermore, QSIs contributed more to the acute toxicity of test binary mixtures. The joint toxic actions of QSIs and SAs were synergism for 23 mixtures, antagonism for 12 mixtures, and addition for 1 mixture. Quantitative structure-activity relationship (QSAR) models for the acute toxicity QSIs, SAs, and their binary mixtures were then constructed based on the lowest CDOCKER interaction energy (Ebind-Luc) between Luc and each chemical and the component proportion in the mixture. These models exhibited good robustness and predictive ability in evaluating the toxicity data and joint toxic actions of QSIs and SAs. This study provides reference data and applicable QSAR models for the environmental risk assessment of QSIs, and gives a new perspective for exploring the joint effects of QSI-antibiotic mixtures.
摘要：
群体感应抑制剂（QSI），作为一种理想的抗生素替代品，已被推荐与传统抗生素联合用于医疗和水产养殖领域。由于环境介质中QSI和抗生素的共存，有必要评估他们的共同风险。然而,关于QSI和抗生素混合物的急性毒性的信息很少。在这项研究中,10个QSI和3个磺胺类药物(SAs，作为传统抗生素的代表)被选为测试化学品，并使用费氏弧菌的生物发光确定了它们的急性毒性作用（A.fischeri)作为终点。结果表明，SAs和QSI均在费氏酵母生物发光中诱导了S形剂量反应。此外，SAs比QSI具有更大的急性毒性，荧光素酶(Luc)可能是测试化学品的靶蛋白。根据每种测试化学品的中值有效浓度(EC50)，根据等毒性(EC50(QSI):EC50(SA)=1:1)和非等毒性比(EC50(QSI):EC50(SA)=1:10、1:5、1:0.2和1:0.1)设计QSI-SA混合物。可以观察到，随着QSI比例的增加，QSI-SA混合物的急性毒性增强，而相应的TU值降低。此外，QSI对测试二元混合物的急性毒性贡献更大。QSI和SAs的联合毒性作用对23种混合物具有协同作用，12种混合物的拮抗作用，并添加1个混合物。急性毒性QSI的定量构效关系(QSAR)模型，SAs,然后根据Luc和每种化学物质之间的最低CDOCKER相互作用能（Ebind-Luc）以及混合物中的组分比例来构建它们的二元混合物。这些模型在评估QSI和SAs的毒性数据和联合毒性作用方面表现出良好的鲁棒性和预测能力。本研究为QSI的环境风险评价提供了参考数据和适用的QSAR模型,并为探索QSI-抗生素混合物的联合作用提供了新的视角。
