氨基糖苷类抗生素与抗菌剂不同毒性比混合对大肠杆菌的联合效应研究
Combined Toxicity of Aminoglycosides and Antimicrobials with Different Ratios on Escherichia coli
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摘要: 抗菌剂的长期滥用导致细菌耐药性问题不断加剧，对人类健康以及生态环境造成了巨大威胁。由于氨基糖苷类抗生素(aminoglycosides, AGs)在临床上应用的广泛性，其与传统抗菌剂和新型抗菌剂在环境中的联合暴露均存在潜在风险。此外，抗菌剂结构、作用机制以及其在混合体系中的占比，都能够影响其与AGs的联合毒性效应。因此，有必要研究AGs与传统抗菌剂和新型抗菌剂以不同毒性比混合的联合毒性效应。本文以大肠杆菌(Escherichia coli, E. coli)为模式生物，以磺胺类(磺胺甲恶唑, SMX)、四环素类(盐酸金霉素, CTC)、大环内酯类(红霉素, ERY)、糖肽类(盐酸万古霉素, VA)和β-内酰胺类(氨苄青霉素, AMP)作为传统抗菌剂的代表，以唑啉类(甲基异噻唑啉酮, MIT)、表面活性剂类(十二烷基三甲基溴化铵, DTAB)和群体感应抑制剂类(3,4-溴2(5H)呋喃酮, DFR)作为新型抗菌剂的代表，测定AGs与抗菌剂在等毒性比时的联合毒性效应。结果表明，AGs与传统抗菌剂中的CTC和VA，以及新型抗菌剂中的DTAB和DFR呈现拮抗的联合毒性作用；AGs与传统抗菌剂中的SMX、ERY和AMP，以及新型抗菌剂中的MIT呈现协同的联合毒性作用。此外，还测试了AGs与产生协同效果的抗菌剂(SMX、ERY、AMP和MIT)在毒性比为1∶5和5∶1下的联合毒性效应。结果显示，AGs与SMX、AMP和MIT在不同毒性比下的联合毒性效应均呈现协同作用，且AGs与抗菌剂的毒性比为1∶5时的协同效果最好，联合暴露的环境风险最大。我们推测，当AGs和能够与其产生协同作用的抗菌剂混合暴露时，混合体系中这种抗菌剂相对于AGs比例的增加，可能使得AGs更容易进入细胞并增强AGs对细菌的毒性作用。本研究能够为今后探索AGs与抗菌剂联合暴露的环境风险评估提供参考。Abstract: The chronically abuse of antibacterial agents has led to a growing problem of bacterial resistance, posing a huge threat to human health and ecological environment. Due to the widely clinical application of aminoglycosides (AGs), the environmental exposure of AGs with traditional antibacterial agents or new antibacterial agents may trigger potential risks on organisms. Furthermore, the structure, the toxic action, and the toxicity ratio of these traditional or new antibacterial agents could all influence their combined effects with AGs. Therefore, it is necessary to investigate the combined toxicity of AGs with traditional or new antibacterial agents at different toxicity ratios. In this study, Escherichia coli (E. coli) was set as the model organism. While sulfonamides (sulfamethoxazole, SMX), tetracyclines (chlorotetracycline hydrochloride, CTC), macrolides (erythromycin, ERY), glycopeptides (vancomycin hydrochloride, VA), and β-lactams (ampicillin, AMP) are representatives of traditional antibacterial agents, azolines (methylisothiazolinone, MIT), surfactants (dodecyl trimethyl ammonium bromide, DTAB) and quorum sensing inhibitors (3,4-dibromo-2-hydroxy-2H-furan-5-one, DFR) are representatives of new antibacterial agents. The combined toxicity of AGs and these agents were tested at equal toxicity ratios. The results showed that AGs exhibited an antagonistic effect with CTC or VA (traditional antibacterial agents), and DTAB or DFR (new antibacterial agents). AGs induced a synergistic effect with SMX, ERY and AMP (traditional antibacterial agents). Meanwhile, there was synergism between AGs and MIT (new antibacterial agents). Because SMX, ERY, AMP and MIT had synergistic effects with AGs on E. coli at 1∶1 toxicity ratio, these agents were chosen to investigate their combined toxicity with AGs at a toxicity ratio of 1∶5 and 5∶1. The results showed that the combined toxicity of AGs with these agents were all synergism at test toxicity ratios. In addition, when the toxicity ratio of AGs with the agents were 1∶5, there exhibited the greatest synergistic effects of the mixtures, indicating the greatest environmental risk. Therefore, it could be speculated that when AGs are exposed with the antibacterial agent that can induce synergistic effects with AGs, the increase of the ratio of this agent in the mixture may make AGs enter cells more easily to enhance their toxic effect on bacteria. This study can provide a reference for future exploring the environmental risk assessment of the combined exposure of AGs and antibacterial agents.
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