去甲二氢愈创木酸通过抑制MCR-1活性和损伤细菌细胞膜，在体内/体外逆转了黏菌素对MCR-1阳性细菌的抗菌活性。

Nordihydroguaiaretic acid reverses the antibacterial activity of colistin against MCR-1-positive bacteria in vivo/in vitro by inhibiting MCR-1 activity and injuring the bacterial cell membrane.

作者信息

Song Ge, Zhou Yonglin, Niu Sen, Deng Xuming, Qiu Jiazhang, Li Li, Wang Jianfeng

机构信息

Department of Respiratory Medicine, the First Hospital of Jilin University, Changchun, China; State Key Laboratory for Zoonotic Diseases, College of Veterinary Medicine, Jilin University, Changchun, China.

State Key Laboratory for Zoonotic Diseases, College of Veterinary Medicine, Jilin University, Changchun, China.

出版信息

Phytomedicine. 2022 Apr;98:153946. doi: 10.1016/j.phymed.2022.153946. Epub 2022 Jan 29.

DOI:10.1016/j.phymed.2022.153946

PMID:35158237

Abstract

BACKGROUND

Colistin (polymyxin E) is an effective antibiotic for the treatment of most multidrug-resistant Gram-negative bacteria. However, some bacteria, including bacterial spp. belonging to the Enterobacteriaceae family, have an acquired resistance against polymyxins, which is attributed to they possess plasmid-carried resistance genes (mcr-1 and its variants). So, there is an urgent need to develop new therapeutic strategies to target broad spectrum resistant spp. from Enterobacteriaceae family in response to the loss of the protective barrier of last-line antibiotics. Here, we report the adjuvant capacity of nordihydroguaiaretic acid (NDGA) for restoring the antibacterial activity of colistin against MCR-1-positive E. coli ZJ487 in vivo/in vitro.

METHODS

A checkerboard assay, time-killing analysis, isobolograms, growth curves and inducible resistance test showed the effect of NDGA combined with colistin in vitro. TLC was used to detect the inhibitory effect of NDGA on MCR-1. Colony determination and hematoxylin and eosin (HE) staining were used to assess the synergistic effect of NDGA and colistin in mice.

RESULTS

Our results showed that NDGA in combination with colistin showed a synergistic bactericidal action without inducing resistance. NDGA directly inhibited MCR-1 activity and resulted in measurable injury to the bacterial cell membrane to recover the antibacterial effect of colistin. Most importantly, NDGA in combination with colistin exhibited an in vivo synergistic effect in murine peritonitis infection models, as evidenced by the survival rate of MCR-1-positive E. coli ZJ487-infected mice which increased from 6.67 to 50.0%.

CONCLUSION

Our study demonstrated that NDGA effectively rescues the efficiency of colistin against MCR-positive E. coli ZJ487 by simultaneously inhibiting both, the MCR activity and the injury to the cell membrane of bacteria.

摘要

背景

黏菌素（多黏菌素E）是治疗大多数耐多药革兰氏阴性菌的有效抗生素。然而，一些细菌，包括肠杆菌科的细菌，对多黏菌素产生了获得性耐药性，这归因于它们拥有质粒携带的耐药基因（mcr-1及其变体）。因此，迫切需要开发新的治疗策略，以应对最后一线抗生素保护屏障的丧失，靶向肠杆菌科的广谱耐药菌。在此，我们报告了去甲二氢愈创木酸（NDGA）在体内/体外恢复黏菌素对MCR-1阳性大肠杆菌ZJ487抗菌活性的佐剂能力。

方法

棋盘法、时间杀菌分析、等效线图、生长曲线和诱导耐药试验显示了NDGA与黏菌素联合在体外的作用。薄层色谱法用于检测NDGA对MCR-1的抑制作用。菌落计数和苏木精-伊红（HE）染色用于评估NDGA和黏菌素在小鼠体内的协同作用。

结果

我们的结果表明，NDGA与黏菌素联合显示出协同杀菌作用且不会诱导耐药性。NDGA直接抑制MCR-1活性，并对细菌细胞膜造成可测量的损伤，从而恢复黏菌素的抗菌效果。最重要的是，NDGA与黏菌素联合在小鼠腹膜炎感染模型中表现出体内协同作用，MCR-1阳性大肠杆菌ZJ487感染小鼠的存活率从6.67%提高到50.0%，证明了这一点。