基于QSAR模型的磺胺与群体感应抑制剂对枯草芽孢杆菌联合慢性毒性规律初探

群体感应抑制剂是抗生素最有可能的替代品,两者在环境中的共存会对生物造成联合毒性影响。以革兰氏阳性菌枯草芽孢杆菌(Bacillus subtilis,B.subtilis)为模式生物,3种群体感应抑制剂(呋喃酮、吡咯酮和吡咯)和磺胺类药物为研究对象,测定了20 h单一和联合毒性。结果显示,3种群体感应抑制剂和磺胺的联合毒性分别表现为相加和拮抗。同时根据不同的联合毒性效应,以药物和蛋白分子的对接结合能(Ebinding)作为结构参数分别构建了联合毒性的QSAR模型,并分析了不同毒性效应下混合物中各组分的相互作用关系。结果表明,无论是相加还是拮抗,在二元混合体系中磺胺与其靶蛋白DHPS的有效结合浓度总是高于群体感应抑制剂与Lux S的有效结合浓度;但当产生拮抗作用时,磺胺与DHPS的有效结合浓度相对较低,推测可能是群体感应抑制剂的存在使得磺胺由分子态变为离子态,从而使其难以穿过细胞壁与DHPS结合导致的。本研究为建立和分析联合毒性的QSAR模型提供了一定的理论基础。

A Preliminary Investigation on the Chronic Single and Mixture Toxicity of Sulfonamides and Quorum Sensing Inhibitors to Bacillus subtilis Based on QSAR

Quorum sensing inhibitors (QSIs) are a promising alternative to the antibiotics, and the coexistence of antibiotics and QSIs could lead to joint toxic effect on ecosystem. Individual and combined toxicity of sulfonamides and QSIs to Bacillus subtilis (B. subtilis) were determined in this study, which showed that the joint toxic action of sulfonamides and QSIs was addition or antagonism. Based on different joint toxic action, QSAR models were developed using the interaction energies (Ebinding) between drugs and related proteins, and the relationships of components in mixtures were discussed, respectively. It was found that effective binding concentration of sulfonamides with its target protein (DHPS) was higher than that of QSIs with LuxS in spite of different joint toxic actions. However, in the case of synergistic effect, effective binding concentration of sulfonamides with DHPS was relatively lower since sulfonamides changed from molecular state to ionic state with the impact of some QSIs, leading to impossible entering into the cell. This study can provide theoretical basis for the establishment and analysis of QSAR models of joint toxicity.