Repurposing Ellipticine Hydrochloride to Combat Colistin-Resistant Extraintestinal Pathogenic E. coli (ExPEC).

Hao Lu,Xiangru Wang,Chenchen Wang,Chen Tan,Manli Liu,Wenqi Dong,Huanchun Chen,Gaoyan Wang,Wenjia Lu

doi:10.3389/fmicb.2020.00806

Abstract

Extraintestinal pathogenic Escherichia coli (ExPEC) strains are the cause of a majority of human extraintestinal infections globally, resulting in enormous direct economic and medical costs. The plasmid-mediated, colistin-resistant gene mcr-1 has broken through the ultimate defense line against MDR Gram-negative pathogens. There is an urgent need to discover the new compound intended for colistin-resistant E. coli. In this study, antibacterial targets of ellipticine hydrochloride (EH) were confirmed by localized surface plasmon resonance (LSPR) and decatenation assay. The LSPR analysis exhibited good binding between EH and E. coli topoisomerase IV. In this study, a synergistic effect is obvious in the combination of EH and colistin, to which eight of ten strains showed synergy, while two isolates (20%) showed no difference. The bacteria enumeration analysis of EH treatment group suggested that the decreased bacterial titer can be observed in various tissues of infected mice. EH treatment significantly decreased the levels of a variety of pro-inflammatory factors, such as TNF-α and IL-6. Moreover, other related lesions, such as inflammatory cell infiltration, alveolar interstitial congestion, and edema were observed to be relieved to different extents. This study reveals the anti-E. coli potential activities and molecular mechanism of EH and the therapeutical effectiveness of EH application to animals. It provides us with a new option for fighting against multidrug-resistant ExPEC infections in the future.

Highlights

Extraintestinal pathogenic Escherichia coli (ExPEC) is a major pathogenic factor for humans and animals
We examined antibacterial activity of ellipticine hydrochloride (EH) with a panel of Grampositive and Gram-negative pathogenic bacterial species and found that EH exhibited potent antibacterial activity against E. coli, S. aureus, K. pneumoniae, S. typhi, and L. monocytogenes, with minimum inhibitory concentration (MIC) ranging from 0.5m to 4 mg/L (Table 1)
Our results showed that 64 mg/L EH inhibited enzyme activity of E. coli topoisomerase IV, manifested by preventing kinetoplast DNA ring from breaking up

Summary

Introduction

Extraintestinal pathogenic Escherichia coli (ExPEC) is a major pathogenic factor for humans and animals. It can cause a variety of extraintestinal diseases, such as neonatal meningitis, sepsis, and urinary tract disease. Ellipticine Hydrochloride Combat Multidrug-Resistant E. coli birds, companion animals, pigs, and humans, etc. Lancet Infectious Diseases reported the first case of plasmidmediated colistin resistance mechanism. The putative structure and action mechanism of mcr-1 and its emergence in enterobacteriaceae of animal and human isolates are described, and the spread of mcr-1 from animals to humans is first proposed (Liu et al, 2016). It is especially urgent to develop new drugs resistant against colistin-resistant E. coli. To shorten the drug development process, the exploitation of already-used drugs was likely to be a feasible method since these existing substances may play a previously unexploited role in a new context (Thangamani et al, 2015)

Methods

Results

Conclusion