抗生素与LED209对大肠杆菌的联合毒性机制

抗生素是一把双刃剑,在提高医疗水平的同时会促进抗性基因的发展。群体感应抑制剂(quorum sensing inhibitors,QSIs)可有效地避免这一缺陷,有望成为抗生素的替代品而与抗生素有环境共存的可能,但目前尚缺乏它们的联合毒性机制及其相关的环境风险评价研究。本文以大肠杆菌为受试生物,测定了群体感应抑制剂N-苯基-4-(3-苯基硫代脲基)苯磺酰胺(LED209)与5种抗生素的单一和二元联合毒性。结果表明,LED209与5种抗生素的联合毒性作用均表现为拮抗,推测是LED209通过影响鞭毛合成,减弱了抗生素对大肠杆菌的生物有效性;同时通过拆分分子式,发现了拮抗作用可能源于LED209分子式中的含苯基和硫代脲基的L1分子,因此建议未来在LED209药物优化时,应尽可能的保留L1部分的基团,从而保证混合体系的最小环境风险。本研究不仅为联合用药提供依据,而且从环境风险评价角度为抗生素替代品LED209的结构优化提供理论指导。

A Preliminary Investigation on the Mechanism for the Combined Toxicity of Antibiotics and LED209 on Escherichia coli

Antibiotics are a double-edged sword that promote the medical level on the one hand and enhance the development of antibiotic resistance genes on the other hand.Quorum sensing inhibitors (QSIs) can effectively avoid the deficiency of antibiotics,and are deemed as a promising substitute for antibiotics.Therefore,the antibiotics and QSIs are likely to coexist in the environment,posing joint effects on the environment.However,the research on the potential risks of their combined exposure is very limited currently.In this paper,a new type of QSI N-phenyl-4-{(phenylamino)thioxomethyl]amino}-benzenesulfonamide (LED209) and five kinds of antibiotics are chosen to study their single and joint effects on Escherichia coli.The results showed that the antibiotics and LED209 presented antagonistic effects on the bacterial growth,which was probably because LED209 could inhibit the synthesis of bacterial flagellum and subsequently weakened the antibacterial activities of the antibiotics.By splitting the structure of LED209 into two parts,it was found that the antagonism between LED209 and the antibiotics was associated to the L1 part that contains phenyl group and thioxomethyl.Therefore,it is recommended that the design of antibacterial drugs should consider including the L1 group,in order to lower the potential risk of their combination with the antibiotics.This study offers a theoretical basis for the combined use of antibiotics and QSIs,and provide theoretical guidance for antibiotics substitutes LED209's structure optimization from the perspective of environmental risk.