Shen Hongyan, Yang Mingru, Wang Jing, Zou Xiaoming, Tong Danqing, Zhang Yulian, Tang Liang, Sun Haoyu, Yang Lei
School of Environmental Science and Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China.
School of Environmental and Material Engineering, Yantai University, Yantai 264005, China.
Sci Total Environ. 2023 Feb 25;861:160574. doi: 10.1016/j.scitotenv.2022.160574. Epub 2022 Nov 29.
The judgment of joint resistance action is significant for evaluating the resistance risk of antibacterial mixture. Using bacterial mutation frequency (MF) and conjugative transfer frequency (CTF) to respectively characterize the bacterial endogenous and exogenous resistance, mutation unit and conjugative transfer unit have been proposed to judge the joint resistance action of antibacterial mixture at a certain dose. However, these methods could not evaluate the antibacterial mixture's joint resistance action at a larger concentration-range. In this study, the concentration addition for bacterial resistance (CA-BR) approach was used to judge the joint resistance actions between kanamycin sulfate (KAN) and some other typical antibacterial agents, including sulfonamides (SAs), sulfonamide potentiators (SAPs), and silver antibacterial compounds (SACs). Through comparing the hormetic dose-response curves of the binary mixtures on the MF (or CTF) in Escherichia coli (E. coli) and the corresponding CA-BR curves calculated from the hormetic dose-responses of the single agents, the joint resistance actions between KAN and other agents were judged to exhibit dose-dependent feature: with the increase of mixture concentration, the joint mutation actions between KAN and SAs (or SAPs) were fixed at synergism, and the joint mutation actions between KAN and SACs varied from antagonism to synergism; the joint conjugative transfer actions between KAN and other agents changed from antagonism to synergism. Mechanistic explanation suggested that the heterogeneous pattern of joint resistance action had a close relationship with the interplays among the agents' modes of action, and meanwhile was significantly influenced by their joint survival pressure on E. coli. This study reveals the dose-dependent feature for the joint resistance action of antibacterial mixture and highlights the importance of exposure concentration, which will benefit clarifying the resistance risk of antibacterial mixture in the environment.
联合抗性作用的判断对于评估抗菌混合物的抗性风险具有重要意义。利用细菌突变频率（MF）和接合转移频率（CTF）分别表征细菌的内源和外源抗性，已提出突变单位和接合转移单位来判断一定剂量下抗菌混合物的联合抗性作用。然而，这些方法无法评估抗菌混合物在更大浓度范围内的联合抗性作用。在本研究中，采用细菌抗性浓度相加（CA-BR）方法来判断硫酸卡那霉素（KAN）与其他一些典型抗菌剂之间的联合抗性作用，这些抗菌剂包括磺胺类药物（SAs）、磺胺增效剂（SAPs）和银抗菌化合物（SACs）。通过比较二元混合物对大肠杆菌中MF（或CTF）的剂量效应曲线以及根据单一药剂的剂量效应计算出的相应CA-BR曲线，判断KAN与其他药剂之间的联合抗性作用呈现剂量依赖性特征：随着混合物浓度的增加，KAN与SAs（或SAPs）之间的联合突变作用固定为协同作用，而KAN与SACs之间的联合突变作用从拮抗作用转变为协同作用；KAN与其他药剂之间的联合接合转移作用从拮抗作用转变为协同作用。机理分析表明，联合抗性作用的异质性模式与药剂作用方式之间的相互作用密切相关，同时也受到它们对大肠杆菌的联合生存压力的显著影响。本研究揭示了抗菌混合物联合抗性作用的剂量依赖性特征，并突出了暴露浓度的重要性，这将有助于阐明环境中抗菌混合物抗性风险。
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