Colistin resistance plasmids dually enhance bacterial virulence and antibiotic resistance via surface polysaccharide biosynthesis

Plasmids carrying the mobilized colistin-resistance gene mcr-1 are prevalent among multidrug-resistant Gram-negative pathogens, yet their broad impact on bacterial physiology and virulence remains unclear. Here, we demonstrate that acquisition of an mcr-1 plasmid concurrently increases antimicrobial resistance and pathogenicity in Escherichia coli. On the same plasmid, the XRE-family transcriptional regulator EcaR cooperates with MCR-1 to activate the wec operon, driving biosynthesis of two surface polysaccharides: enterobacterial common antigen (ECA) and a high-molecular-weight O-chain. Expression of these surface polysaccharides increases bile resistance and virulence in a murine model and further elevates colistin resistance. MCR-1 enhances transcription of upstream genes in the wec operon, whereas EcaR directly activates an internal promoter (PwecE) to induce downstream gene expression. Thus, both components are required for surface polysaccharide expression, and deletion of either abolishes the phenotype. Genomic analysis of publicly available mcr plasmids reveals widespread co-occurrence of mcr-1 and ecaR on IncI2 and IncX4 plasmids, indicating their functional complementarity. These findings uncover a mechanism by which resistance plasmids remodel the bacterial surface, linking horizontal gene transfer to coordinated regulation of antimicrobial resistance and virulence. In this work, authors show that colistin-resistance plasmids in Escherichia coli, via MCR-1 and a plasmid-encoded regulator, upregulate surface polysaccharide synthesis, enhancing antibiotic resistance and virulence and defining a mechanistic link between resistance and pathogenicity.

• Publication year

  2025

• Venue

  Nature Communications

• Publication date

  2025-11-12

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/s41467-025-65412-9PMID 41224769PMCID 12612032
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Host- plasmid network structure in wastewater is linked to antimicrobial resistance genes

  2024cited by this paper
• Characterization of two novel colistin resistance gene mcr-1 variants originated from Moraxella spp.

  2023cited by this paper
• Fitness effects of plasmids shape the structure of bacteria–plasmid interaction networks

  2022cited by this paper
• Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis

  2022cited by this paper
• Subcellular localization of the enterobacterial common antigen GT‐E‐like glycosyltransferase, WecG

  2022cited by this paper
• Role of mobile genetic elements in the global dissemination of the carbapenem resistance gene blaNDM

  2022cited by this paper
• PixR, a Novel Activator of Conjugative Transfer of IncX4 Resistance Plasmids, Mitigates the Fitness Cost of mcr-1 Carriage in Escherichia coli

  2021cited by this paper
• ElyC and Cyclic Enterobacterial Common Antigen Regulate Synthesis of Phosphoglyceride-Linked Enterobacterial Common Antigen

  2021cited by this paper
• Genetic Analysis of mcr-1-Carrying Plasmids From Gram-Negative Bacteria in a Dutch Tertiary Care Hospital: Evidence for Intrapatient and Interspecies Transmission Events

  2021cited by this paper
• Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane.

  2021cited by this paper
• A ProQ/FinO family protein involved in plasmid copy number control favours fitness of bacteria carrying mcr-1-bearing IncI2 plasmids

  2021cited by this paper
• Lipopolysaccharide-Linked Enterobacterial Common Antigen (ECALPS) Occurs in Rough Strains of Escherichia coli R1, R2, and R4

  2020cited by this paper
• Multidrug-Resistant Bacteria in the Community: An Update.

  2020cited by this paper
• Population genomics of Klebsiella pneumoniae

  2020cited by this paper
• Colistin and its role in the Era of antibiotic resistance: an extended review (2000–2019)

  2020cited by this paper
• Comparison of Fitness Cost and Virulence in Chromosome- and Plasmid-Mediated Colistin-Resistant Escherichia coli

  2020cited by this paper
• Identification of mobile colistin resistance genes (mcr-1.1, mcr-5, mcr-8.1) in Enterobacteriaceae and Alcaligenes faecalis of human and animal origins, Nigeria.

  2020cited by this paper
• Enterobacterial Common Antigen: Synthesis and Function of an Enigmatic Molecule

  2020cited by this paper
• Nonclonal Emergence of Colistin Resistance Associated with Mutations in the BasRS Two-Component System in Escherichia coli Bloodstream Isolates

  2019cited by this paper
• Characterization of mcr-1-Harboring Plasmids from Pan Drug-Resistant Escherichia coli Strains Isolated from Retail Raw Chicken in South Korea

  2019influential reference
• Epidemiologic and genomic insights on mcr-1-harbouring Salmonella from diarrhoeal outpatients in Shanghai, China, 2006–2016

  2019cited by this paper
• Cyclic Enterobacterial Common Antigen Maintains the Outer Membrane Permeability Barrier of Escherichia coli in a Manner Controlled by YhdP

  2018cited by this paper
• Function and Biogenesis of Lipopolysaccharides

  2018cited by this paper
• Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane

  2018cited by this paper
• The use of polymyxins to treat carbapenem resistant infections in neonates and children

  2018cited by this paper
• Mobile Genetic Elements Associated with Antimicrobial Resistance

  2018cited by this paper
• Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1

  2017influential reference
• Interactions between Bacteria and Bile Salts in the Gastrointestinal and Hepatobiliary Tracts

  2017cited by this paper
• Prevalence of mcr-1 in Escherichia coli and Klebsiella pneumoniae recovered from bloodstream infections in China: a multicentre longitudinal study.

  2017cited by this paper
• High Rate of MCR-1–Producing Escherichia coli and Klebsiella pneumoniae among Pigs, Portugal

  2017cited by this paper
• mcr-1−Harboring Salmonella enterica Serovar Typhimurium Sequence Type 34 in Pigs, China

  2017cited by this paper
• Balancing mcr-1 expression and bacterial survival is a delicate equilibrium between essential cellular defence mechanisms

  2017cited by this paper
• The global distribution and spread of the mobilized colistin resistance gene mcr-1

  2017influential reference
• Global phylogenetic analysis of Escherichia coli and plasmids carrying the mcr-1 gene indicates bacterial diversity but plasmid restriction

  2017cited by this paper
• Escherichia coli Harboring mcr-1 and blaCTX-M on a Novel IncF Plasmid: First Report of mcr-1 in the United States

  2016cited by this paper
• Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study.

  2016influential reference
• Dissemination and Mechanism for the MCR-1 Colistin Resistance

  2016influential reference
• Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It.

  2015cited by this paper
• Roary: rapid large-scale prokaryote pan genome analysis

  2015cited by this paper
• Molecular mechanisms of antibiotic resistance

  2014cited by this paper
• Supplementary Information

  2014cited by this paper
• Biosynthesis and export of bacterial lipopolysaccharides.

  2014cited by this paper
• Plasmids and the spread of resistance.

  2013cited by this paper
• Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis

  2013cited by this paper
• Spontaneous and transient defence against bacteriophage by phase‐variable glucosylation of O‐antigen in Salmonella enterica serovar Typhimurium

  2012cited by this paper
• Characterization of anti-ECA antibodies in rabbit antiserum against rough Yersinia enterocolitica O:3

  2011cited by this paper
• The bacterial cell envelope.

  2010cited by this paper
• Outer membrane permeability and antibiotic resistance.

  2009cited by this paper
• The antibiotic resistome: the nexus of chemical and genetic diversity

  2007cited by this paper
• Altering the Length of the Lipopolysaccharide O Antigen Has an Impact on the Interaction of Salmonella enterica Serovar Typhimurium with Macrophages and Complement

  2006cited by this paper
• The interaction between bacteria and bile.

  2005cited by this paper
• Characterization and investigation of substrate specificity of the sugar aminotransferase WecE from E. coli K12.

  2004cited by this paper
• The PmrA-Regulated pmrC Gene Mediates Phosphoethanolamine Modification of Lipid A and Polymyxin Resistance in Salmonella enterica

  2004cited by this paper
• Publisher's Note

  2003cited by this paper
• O-antigen structural variation: mechanisms and possible roles in animal/plant-microbe interactions.

  2001cited by this paper
• One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products.

  2000cited by this paper
• Methods for generating precise deletions and insertions in the genome of wild-type Escherichia coli: application to open reading frame characterization

  1997cited by this paper
• A Role for Exopolysaccharides in the Protection of Microorganisms from Desiccation

  1994cited by this paper
• ECA, the enterobacterial common antigen.

  1988influential reference
• Comparison of enterobacterial common antigen from different species by serological techniques.

  1987cited by this paper
• Biosynthesis of enterobacterial common antigen

  1985cited by this paper
• Monoclonal antibodies to enterobacterial common antigen and to Escherichia coli lipopolysaccharide outer core: demonstration of an antigenic determinant shared by enterobacterial common antigen and E. coli K5 capsular polysaccharide

  1985cited by this paper
• Available

  1984cited by this paper
• The enterobacterial common-antigen, a cyclic polysaccharide.

  1984cited by this paper
• Effect of proteins on the immunogenicity of enterobacterial common antigen

  1981cited by this paper
• Structural studies on the immunogenic form of the enterobacterial common antigen.

  1978cited by this paper
• The role of the bacterial cell envelope in antibiotic resistance.

  1975cited by this paper
• Evidence for a Common Hapten Associated with Endotoxin Fractions of E. coli and other Enterobacteriaceae. ∗

  1962cited by this paper

• No citing papers are available for this paper.