The irrational use of broad-spectrum antibiotics has led to increasing resistance of bacteria to antibiotics, and the emergence of the plasmid-mediated colistin resistance gene mcr-1 has led to the dilemma of infections with no available cure. Here, we have found a potential MCR-1 inhibitor for use against infections caused by MCR-1 positive resistant bacteria. A checkerboard MIC (minimum inhibitory concentration) assay, growth curve assay, kill curve assay, cytotoxicity assay, molecular dynamics simulation analysis, Western blot assay and mouse pneumonia model in vivo protection rate assay were used to evaluate the synergy effect between genistein and polymyxins. The results showed that genistein could restore the bactericidal activity against MCR-1-positive strains for which there was no antibacterial activity, and reduce the bacterial load to some extent. Genistein does not inhibit the expression of MCR-1, but inhibits the binding of MCR-1 to its substrate by binding to the amino acids of the active region of MCR-1, thereby inhibiting the biological activity of MCR-1. The in vivo results also showed that the protection rate of mice treated with the combination therapy of genistein and polymyxins increased by 20% compared to that of mice treated with polymyxins alone. Our results confirm that genistein is an inhibitor of MCR-1 and promote its potential use in combination with polymyxins to treat severe infections caused by MCR-1 positive Enterobacteriaceae.

中文翻译：

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MCR-1 的潜在抑制剂：增强多粘菌素对多药耐药细菌功效的尝试

广谱抗生素的不合理使用导致细菌对抗生素的耐药性不断增强，而质粒介导的粘菌素耐药基因mcr-1的出现则导致了感染无药可治的困境。在这里，我们发现了一种潜在的 MCR-1 抑制剂，可用于对抗由 MCR-1 阳性耐药细菌引起的感染。采用棋盘MIC（最低抑菌浓度）测定、生长曲线测定、杀伤曲线测定、细胞毒性测定、分子动力学模拟分析、Western印迹测定和小鼠肺炎模型体内保护率测定来评价染料木黄酮与多粘菌素之间的协同作用。结果表明，金雀异黄素可以恢复对无抗菌活性的MCR-1阳性菌株的杀菌活性，并在一定程度上减少细菌负荷。染料木素不抑制MCR-1的表达，而是通过与MCR-1活性区的氨基酸结合来抑制MCR-1与其底物的结合，从而抑制MCR-1的生物活性。体内结果还显示，与单独使用多粘菌素治疗的小鼠相比，使用染料木素和多粘菌素联合治疗的小鼠的保护率提高了20%。我们的结果证实，染料木黄酮是 MCR-1 的抑制剂，并促进其与多粘菌素联合治疗由 MCR-1 阳性肠杆菌科细菌引起的严重感染的潜在用途。从而抑制 MCR-1 的生物活性。体内结果还显示，与单独使用多粘菌素治疗的小鼠相比，使用染料木素和多粘菌素联合治疗的小鼠的保护率提高了20%。我们的结果证实，染料木黄酮是 MCR-1 的抑制剂，并促进其与多粘菌素联合治疗由 MCR-1 阳性肠杆菌科细菌引起的严重感染的潜在用途。从而抑制 MCR-1 的生物活性。体内结果还显示，与单独使用多粘菌素治疗的小鼠相比，使用染料木素和多粘菌素联合治疗的小鼠的保护率提高了20%。我们的结果证实，染料木黄酮是 MCR-1 的抑制剂，并促进其与多粘菌素联合治疗由 MCR-1 阳性肠杆菌科细菌引起的严重感染的潜在用途。