Clinical Resistome Screening of 1,110 Escherichia coli Isolates Efficiently Recovers Diagnostically Relevant Antibiotic Resistance Biomarkers and Potential Novel Resistance Mechanisms.
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Authors
Volz, CarstenRamoni, Jonas
Beisken, Stephan
Galata, Valentina
Keller, Andreas
Plum, Achim
Posch, Andreas E
Müller, Rolf
Issue Date
2019-01-01
Metadata
Show full item recordAbstract
Multidrug-resistant pathogens represent one of the biggest global healthcare challenges. Molecular diagnostics can guide effective antibiotics therapy but relies on validated, predictive biomarkers. Here we present a novel, universally applicable workflow for rapid identification of antimicrobial resistance (AMR) biomarkers from clinical Escherichia coli isolates and quantitatively evaluate the potential to recover causal biomarkers for observed resistance phenotypes. For this, a metagenomic plasmid library from 1,110 clinical E. coli isolates was created and used for high-throughput screening to identify biomarker candidates against Tobramycin (TOB), Ciprofloxacin (CIP), and Trimethoprim-Sulfamethoxazole (TMP-SMX). Identified candidates were further validated in vitro and also evaluated in silico for their diagnostic performance based on matched genotype-phenotype data. AMR biomarkers recovered by the metagenomics screening approach mechanistically explained 77% of observed resistance phenotypes for Tobramycin, 76% for Trimethoprim-Sulfamethoxazole, and 20% Ciprofloxacin. Sensitivity for Ciprofloxacin resistance detection could be improved to 97% by complementing results with AMR biomarkers that are undiscoverable due to intrinsic limitations of the workflow. Additionally, when combined in a multiplex diagnostic in silico panel, the identified AMR biomarkers reached promising positive and negative predictive values of up to 97 and 99%, respectively. Finally, we demonstrate that the developed workflow can be used to identify potential novel resistance mechanisms.Citation
Front Microbiol. 2019 Aug 13;10:1671. doi: 10.3389/fmicb.2019.01671. eCollection 2019.Affiliation
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.Publisher
FrontiersJournal
Frontiers in MicrobiologyPubMed ID
31456751Type
ArticleLanguage
enISSN
1664-302Xae974a485f413a2113503eed53cd6c53
10.3389/fmicb.2019.01671
Scopus Count
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- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International
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