Li Peng-Cheng, Tong Yin-Chao, Xiao Xing-Lan, Fan Yun-Peng, Ma Wu-Ren, Liu Ying-Qiu, Zhuang Shen, Qing Su-Zhu, Zhang Wei-Min
College of Veterinary Medicine, Northwest A&F University, Yangling, China.
Institute of Traditional Chinese Veterinary Medicine, Northwest A&F University, Yangling, China.
Front Microbiol. 2024 Dec 11;15:1474919. doi: 10.3389/fmicb.2024.1474919. eCollection 2024.
The development of extended-spectrum-beta-lactamase (ESBLs) () has become a global threat to public health. An alternative strategy to alleviate this is identifying potential natural compounds to restore antibiotic activity against ESBLs . This study aimed to find a possible compound to restore ESBLs sensitivity to ceftiofur.
The synergistic effect of kaempferol and ceftiofur against ESBLs was investigated by checkerboard assays, time-kill, growth curves, and scanning electronic microscope. The impact of kaempferol with ceftiofur on the biofilm of ESBLs was evaluated by crystal violet staining and laser scanning confocal microscopy and this study also assessed the effect of kaempferol on the initial adhesion and aggregation of (SY20) by examining motility, adhesion, and surface characteristics. The RT-qPCR was used to determine the effect of kaempferol on the expression of genes related to the /AI-2 quorum sensing system in ESBLs , and the effect of kaempferol on AI-2 signaling molecules was determined by molecular docking and bioassay. The impact of kaempferol on the activity of protein was determined by RT-qPCR, molecular docking, and nitrofen experiments, the results were further verified by transcriptome analysis. The mouse infection model was established, and the inhibitory mechanism of kaempferol with ceftiofur on bacteria in vivo was further verified by HE staining and immunohistochemistry.
Kaempferol with ceftiofur exerts synergistic antibacterial and bactericidal effects on ESBLs by influencing β-lactamase activity, biofilm formation, and /AI-2 QS system. In vivo, kaempferol protected the small intestinal villi from the damage of ESBLs . Furthermore, kaempferol fully restores the activity of ceftiofur in animal infection models by relieving the TLR/NF-κb pathway. In conclusion, the sensitivity of ESBLs to ceftiofur in vitro and in vivo could be enhanced by kaempferol, which showed that kaempferol may be a kind of antibiotic adjuvant.
超广谱β-内酰胺酶（ESBLs）的出现已成为对公共卫生的全球威胁。缓解这一问题的一种替代策略是鉴定潜在的天然化合物，以恢复抗生素对ESBLs的活性。本研究旨在寻找一种可能恢复ESBLs对头孢噻呋敏感性的化合物。
通过棋盘法、时间杀菌曲线、生长曲线和扫描电子显微镜研究山奈酚与头孢噻呋对ESBLs的协同作用。通过结晶紫染色和激光扫描共聚焦显微镜评估山奈酚与头孢噻呋对ESBLs生物膜的影响，本研究还通过检测运动性、黏附性和表面特征评估山奈酚对[具体细菌名称未给出，推测为文中的ESBLs产生菌]（SY20）初始黏附和聚集的影响。采用RT-qPCR确定山奈酚对ESBLs中与[具体信号通路未给出，推测为文中提到的某信号通路] /AI-2群体感应系统相关基因表达的影响，通过分子对接和生物测定确定山奈酚对AI-2信号分子的影响。通过RT-qPCR、分子对接和硝基芬实验确定山奈酚对[具体蛋白未给出，推测为文中提到的某蛋白]蛋白活性的影响，结果通过转录组分析进一步验证。建立小鼠感染模型，通过HE染色和免疫组化进一步验证山奈酚与头孢噻呋在体内对细菌的抑制机制。
山奈酚与头孢噻呋通过影响β-内酰胺酶活性、生物膜形成和[具体信号通路未给出，推测为文中提到的某信号通路] /AI-2 QS系统，对ESBLs发挥协同抗菌和杀菌作用。在体内，山奈酚保护小肠绒毛免受ESBLs的损伤。此外，山奈酚通过缓解TLR/NF-κb通路，在动物感染模型中完全恢复头孢噻呋的活性。总之，山奈酚可增强ESBLs在体外和体内对头孢噻呋的敏感性，表明山奈酚可能是一种抗生素佐剂。
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