Diversification and evolution of vancomycin-resistant Enterococcus faecium during intestinal domination Journal Article


Authors: Dubin, K. A.; Mathur, D.; McKenney, P. T.; Taylor, B. P.; Littmann, E. R.; Peled, J. U.; Van Den Brink, M. R. M.; Taur, Y.; Pamer, E. G.; Xavier, J. B.
Article Title: Diversification and evolution of vancomycin-resistant Enterococcus faecium during intestinal domination
Abstract: Vancomycin-resistant Enterococcus faecium (VRE) is a leading cause of hospital-acquired infections. This is particularly true in immunocompromised patients, where the damage to the microbiota caused by antibiotics can lead to VRE domination of the intestine, increasing a patient's risk for bloodstream infection. In previous studies we observed that the intestinal domination by VRE of patients hospitalized to receive allogeneic bone marrow transplantation can persist for weeks, but little is known about subspecies diversification and evolution during prolonged domination. Here we combined a longitudinal analysis of patient data and in vivo experiments to reveal previously unappreciated subspecies dynamics during VRE domination that appeared to be stable from 16S rRNA microbiota analyses. Whole-genome sequencing of isolates obtained from sequential stool samples provided by VRE-dominated patients revealed an unanticipated level of VRE population complexity that evolved over time. In experiments with ampicillin-treated mice colonized with a single CFU, VRE rapidly diversified and expanded into distinct lineages that competed for dominance. Mathematical modeling shows that in vivo evolution follows mostly a parabolic fitness landscape, where each new mutation provides diminishing returns and, in the setting of continuous ampicillin treatment, reveals a fitness advantage for mutations in penicillin-binding protein 5 (pbp5) that increase resistance to ampicillin. Our results reveal the rapid diversification of host-colonizing VRE populations, with implications for epidemiologic tracking of in-hospital VRE transmission and susceptibility to antibiotic treatment. Copyright © 2019 Dubin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Keywords: controlled study; antibiotic therapy; single nucleotide polymorphism; nonhuman; mouse; animal experiment; animal model; gene locus; genetic variability; genotype; allogenic bone marrow transplantation; molecular evolution; amplicon; abc transporter; dna sequence; alanine; vancomycin resistant enterococcus; bacterial genome; intestine flora; computer model; gamma glutamyltransferase; rna 16s; bacterial dna; population dynamics; aspartic acid; enterococcal infection; longitudinal study; rna sequence; enterococcus faecium; clone; bacterial mutation; phylogenetic tree; bacterial rna; ampicillin; metagenome; microbial diversity; chromosome variant; indel mutation; genetic difference; metagenomics; human; female; priority journal; article; whole genome sequencing; contig; bacterial evolution; multilocus sequence typing; penicillin binding protein 5; subspecies
Journal Title: Infection and Immunity
Volume: 87
Issue: 7
ISSN: 0019-9567
Publisher: American Society for Microbiology  
Date Published: 2019-07-01
Start Page: e00102-19
Language: English
DOI: 10.1128/iai.00102-19
PUBMED: 31010813
PROVIDER: scopus
PMCID: PMC6589067
DOI/URL:
Notes: Article -- Export Date: 2 August 2019 -- Source: Scopus
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MSK Authors
  1. Eric Pamer
    253 Pamer
  2. Joao Debivar Xavier
    56 Xavier
  3. Ying Taur
    90 Taur
  4. Krista Dubin
    5 Dubin
  5. Jonathan U Peled
    48 Peled
  6. Bradford P Taylor
    2 Taylor
  7. Deepti Mathur
    1 Mathur