Comprehensive proteomic and metabolomic profiling of mcr-1-mediated colistin resistance in Escherichia coli

Hui Li,Yingyu Wang,Qingshi Meng,Yang Wang,Guoliang Xia,Xi Xia,Jianzhong Shen

doi:10.1016/j.ijantimicag.2019.02.014

Abstract

Spread of the mcr-1 gene in human and veterinary medicine has jeopardised the use of polymyxins, last-resort antibiotics against life-threatening multidrug-resistant Gram-negative bacteria. As a lipid-modifying gene, whether mcr-1 causes proteomic and metabolomic changes in bacteria and affects the corresponding metabolic pathway is largely unknown. In this study, label-free quantitative proteomics and untargeted metabolomics were used to profile comprehensive proteome and metabolome characteristics of mcr-1-mediated colistin-resistant and -susceptible Escherichia coli in order to gain further insight into the colistin resistance mechanism. Large sets of differentially expressed proteins (DEPs) and metabolites were identified that contributed to mcr-1-mediated antimicrobial resistance, predominantly in different growth conditions with and without colistin. mcr-1 caused downregulated expression of most proteins in order to adapt to drug pressure. Pathway analysis showed that metabolic processes were significantly affected, mainly related to glycerophospholipid metabolism, thiamine metabolism and lipopolysaccharide (LPS) biosynthesis. The substrate phosphoethanolamine (PEA) for mcr-1 to mediate colistin resistance was accumulated in colistin-resistant E. coli. Notably, mcr-1 not only caused PEA modification of the bacterial cell membrane lipid A but also affected the biosynthesis and transport of lipoprotein in colistin resistance by disturbing the expression of efflux pump proteins involved in the cationic antimicrobial peptide (CAMP) resistance pathway. Overall, disturbed glycerophospholipid metabolism and LPS biosynthesis as well as accumulation of the substrate PEA was closely related with mcr-1-mediated colistin resistance. These findings could provide further valuable information to inhibit colistin resistance by blocking this metabolic process.

Highlights

Resistance to polymyxins has emerged worldwide threatening the efficacy of the last-resort antimicrobials used for the treatment of multidrug-resistant (MDR)Enterobacteriaceae infection in humans [1, 2]
Many excellent achievements in its epidemic evidence and resistance mechanism have been made, the in-depth colistin resistance mechanisms, such as the omics profile of bacteria mediated by mcr-1 in Escherichia coli needs further research
Comprehensive proteomic and metabolomic profiles of mcr-1-mediated colistin-resistant and -sensitive Escherichia coli were investigated to clarify the protein and metabolite features related to mcr-1

Summary

Introduction

Resistance to polymyxins has emerged worldwide threatening the efficacy of the last-resort antimicrobials used for the treatment of multidrug-resistant (MDR)Enterobacteriaceae infection in humans [1, 2]. Colistin resistance can be mediated by phosphoethanolamine (PEA) or 4-amino-arabinose modification of lipid A that abolishes the initial electrostatic interaction with polymyxins [4, 5]. Mcr-1 was the firstly reported plasmid-mediated colistin resistance gene and encoded a member of the family of PEA transferases that decorated the lipid A headgroups of lipopolysaccharide (LPS) with PEA [6]. The resistance rate of mcr-1 increased rapidly, and the gene has the risk of entering the human body from the food chain, which is a serious threat to human health and public health security [14, 15]. Since the mcr-1 gene was reported, many studies clearly clarified the status quo of its transmission and provided its epidemic evidence in food, livestock and human [16-

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