Abstract

Bacterial resistance to antibiotics is an increasing threat to global healthcare systems. We therefore sought compounds with potential to reverse antibiotic resistance in a clinically relevant multi-drug resistant isolate of Escherichia coli (NCTC 13400). 200 natural compounds with a history of either safe oral use in man, or as a component of a traditional herb or medicine, were screened. Four compounds; ellagic acid, propyl gallate, cinchonidine and cepharanthine, lowered the minimum inhibitory concentrations (MICs) of tetracycline, chloramphenicol and tobramycin by up to fourfold, and when combined up to eightfold. These compounds had no impact on the MICs of ampicillin, erythromycin or trimethoprim. Mechanistic studies revealed that while cepharanthine potently suppressed efflux of the marker Nile red from bacterial cells, the other hit compounds slowed cellular accumulation of this marker, and/or slowed bacterial growth in the absence of antibiotic. Although cepharanthine showed some toxicity in a cultured HEK-293 mammalian cell-line model, the other hit compounds exhibited no toxicity at concentrations where they are active against E. coli NCTC 13400. The results suggest that phytochemicals with capacity to reverse antibiotic resistance may be more common in traditional medicines than previously appreciated, and may offer useful scaffolds for the development of antibiotic-sensitising drugs.

Graphic Abstract

中文翻译：

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头孢硫胺，金鸡尼定，鞣花酸和没食子酸丙酯在多药耐药大肠杆菌中逆转四环素耐药性

摘要

细菌对抗生素的耐药性对全球医疗保健系统的威胁日益增加。因此，我们在临床相关的多药耐药大肠杆菌中寻找具有逆转抗生素耐药性潜力的化合物（NCTC 13400）。筛选了200种历史悠久的天然化合物，这些化合物既可以在人体内安全使用，也可以作为传统草药或药物的成分使用。四种化合物；鞣花酸，没食子酸丙酯，辛可尼定和头孢兰定可使四环素，氯霉素和妥布霉素的最低抑菌浓度（MICs）降低多达四倍，而当降低至八倍时。这些化合物对氨苄青霉素，红霉素或甲氧苄啶的MIC均无影响。机理研究表明，虽然头孢兰氨酸有效抑制了标记尼罗红从细菌细胞中的流出，但其他命中化合物在没有抗生素的情况下减慢了该标记的细胞积累和/或减缓了细菌的生长。尽管头孢兰定在培养的HEK-293哺乳动物细胞系模型中显示出一定的毒性，大肠杆菌NCTC13400。结果表明，具有逆转抗生素抗性能力的植物化学物质在传统药物中可能比以前认识到的更为常见，并且可能为开发抗生素敏感性药物提供有用的支架。

图形摘要