Artesunate, EDTA and colistin work synergistically against MCR-negative and -positive colistin-resistant Salmonella

Author:

Zhai Yajun1,Liu Peiyi1,Hu Xueqin1,Fan Changjian1,Cui Xiaodie1,He Qibiao1,He Dandan1,Ma Xiaoyuan1,Hu Gongzheng1,Zhai Yajun1ORCID

Affiliation:

1. Department of Pharmacology and Toxicology, College of Veterinary Medicine, Henan Agricultural University

Abstract

Discovering new strategies to combat the multi-drug resistance bacteria constitutes a major medical challenge of our time. Previously, artesunate (AS) has been reported to exert antibacterial enhancement activity in combination with β-lactam antibiotics, via inhibition of the efflux pump AcrB. However, combination of AS and colistin (COL) revealed weak synergistic effect against a limited number of strains, and few studies have further explored its possible mechanism of synergistic action. In this paper, we found that AS and EDTA could strikingly enhance the antibacterial effects of COL against mcr - 1 − and mcr - 1 + Salmonella strains either in vitro or in vivo , when used in triple combination. The excellent bacteriostatic effect was primarily related to the increased cell membrane damage, accumulation of toxic compounds and inhibition of MCR-1. The potential binding sites of AS to MCR-1 (THR283, SER284, and TYR287) were critical for its inhibition of MCR-1 activity. Additionally, we also demonstrated that the CheA of chemosensory system and virulence-related protein SpvD were critical for the bacteriostatic synergistic effects of the triple combination. Selectively targeting CheA, SpvD or MCR using the natural compound artesunate could be further investigated as an attractive strategy for treatment of Salmonella infection. Collectively, our work opens up avenues towards the potentiation of colistin and revealed an alternative drug combination strategy to overcome COL resistant bacterial infections.

Publisher

eLife Sciences Publications, Ltd

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3