The Attenuated Protective Effect of Outer Membrane Vesicles Produced by a mcr-1 Positive Strain on Colistin Sensitive Escherichia coli.

Xue Li,Xiukun Wang,Congran Li,Xinxin Hu,Tongying Nie,Xinyi Yang,Xuefu You,Lang Sun,Youwen Zhang

doi:10.3389/fcimb.2021.701625

Abstract

Resistance to colistin, especially mobilized colistin resistance (mcr), is a serious threat to public health since it may catalyze a return of the “pre-antibiotic era”. Outer membrane vesicles (OMVs) play a role in antibiotic resistance in various ways. Currently, how OMVs participate in mcr-1-mediated colistin resistance has not been established. In this study, we showed that both OMVs from the mcr-1 negative and positive Escherichia coli (E. coli) strains conferred dose-dependent protection from colistin. However, OMVs from the mcr-1 positive strain conferred attenuated protection when compared to the OMVs of a mcr-1 negative strain at the same concentration. The attenuated protective effect of OMVs was related to the reduced ability to absorb colistin from the environment, thus promoting the killing of colistin sensitive E. coli strains. Lipid A modified with phosphoethanolamine was presented in the OMVs of the mcr-1 positive E. coli strain and resulted in decreased affinity to colistin and less protection. Meanwhile, E. coli strain carrying the mcr-1 gene packed more unmodified lipid A in OMVs and kept more phosphoethanolamine modified lipid A in the bacterial cells. Our study provides a first glimpse of the role of OMVs in mcr-1 -mediated colistin resistance.

Highlights

Infections caused by multidrug-resistant (MDR) Gram-negative bacteria have led to the rebirth of the “last-line” antibiotic colistin
The nanoparticle tracking analysis (NTA) of the Outer membrane vesicles (OMVs) determined that the median diameters were 134.2 and 124.9 nm for OMVs isolated from E. coli 08-85 and E. coli K12 respectively (Figures 1C, D)
The uptake of NPN by OMVs of E. coli 50434 was less than that of E. coli K12 OMVs (Figure S1). These results suggested OMVs of E. coli K12 absorbed more colistin than OMVs of E. coli 50434 at the same concentration and could explain the attenuated protection provided by OMVs of mcr-1 positive E. coli strains

Summary

Introduction

Infections caused by multidrug-resistant (MDR) Gram-negative bacteria have led to the rebirth of the “last-line” antibiotic colistin. The most identified mechanism of resistance to colistin in Gram-negative bacteria involves modifications to the LPS which consists of the O antigen, the core oligosaccharide and the lipid A moiety (Nikaido, 2003). In E. coli, modification of lipid A with 4amino-4-deoxy-L-arabinose, phosphoethanolamine (pEtN) and/or galactosamine results in a reduced negative charge of LPS and reduced interaction between colistin and the LPS (Breazeale et al, 2005; Chen and Groisman, 2013; Moffatt et al, 2019). In E. coli, expression of the mcr-1 gene results in the addition of phosphoethanolamine to lipid A and resistance to colistin (Ling et al, 2020)

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Results

Conclusion