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Genome reconstruction and characterisation of extensively drug-resistant bacterial pathogens through direct metagenomic sequencing of human faeces

Andre Mu, Jason C. Kwong, Nicole S. Isles, Anders Gonçalves da Silva, Mark B. Schultz, Susan A. Ballard, Glen P. Carter, Deborah A. Williamson, Torsten Seemann, Timothy P. Stinear, Benjamin P. Howden
doi: https://doi.org/10.1101/153874
Andre Mu
1Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
2Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
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Jason C. Kwong
1Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
2Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
3Department of Infectious Diseases, Austin Health, Australia
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Nicole S. Isles
1Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
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Anders Gonçalves da Silva
1Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
2Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
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Mark B. Schultz
1Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
2Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
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Susan A. Ballard
1Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
2Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
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Glen P. Carter
2Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
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Deborah A. Williamson
1Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
2Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
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Torsten Seemann
2Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
4Melbourne Bioinformatics, University of Melbourne, Australia
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Timothy P. Stinear
2Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
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Benjamin P. Howden
1Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
2Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia
3Department of Infectious Diseases, Austin Health, Australia
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Abstract

Whole-genome sequencing of microbial pathogens is revolutionising modern approaches to outbreaks of infectious diseases and is reliant upon organism culture. Culture-independent methods have shown promise in identifying pathogens, but high level reconstruction of microbial genomes from microbiologically complex samples for more in-depth analyses remains a challenge. Here, using metagenomic sequencing of a human faecal sample and analysis by tetranucleotide frequency profiling projected onto emergent self-organising maps, we were able to reconstruct the underlying populations of two extensively-drug resistant pathogens, Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae and vancomycin-resistant Enterococcus faecium. From these genomes, we were able to ascertain molecular typing results, such as MLST, and identify highly discriminatory mutations in the metagenome to distinguish closely related strains. These proof-of-principle results demonstrate the utility of clinical sample metagenomics to recover sequences of important drug-resistant bacteria and application of the approach in outbreak investigations, independent of the need to culture the organisms.

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Posted June 22, 2017.
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Genome reconstruction and characterisation of extensively drug-resistant bacterial pathogens through direct metagenomic sequencing of human faeces
Andre Mu, Jason C. Kwong, Nicole S. Isles, Anders Gonçalves da Silva, Mark B. Schultz, Susan A. Ballard, Glen P. Carter, Deborah A. Williamson, Torsten Seemann, Timothy P. Stinear, Benjamin P. Howden
bioRxiv 153874; doi: https://doi.org/10.1101/153874
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Genome reconstruction and characterisation of extensively drug-resistant bacterial pathogens through direct metagenomic sequencing of human faeces
Andre Mu, Jason C. Kwong, Nicole S. Isles, Anders Gonçalves da Silva, Mark B. Schultz, Susan A. Ballard, Glen P. Carter, Deborah A. Williamson, Torsten Seemann, Timothy P. Stinear, Benjamin P. Howden
bioRxiv 153874; doi: https://doi.org/10.1101/153874

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