Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis

Nature Communications
Phelim BradleyZamin Iqbal

Abstract

The rise of antibiotic-resistant bacteria has led to an urgent need for rapid detection of drug resistance in clinical samples, and improvements in global surveillance. Here we show how de Bruijn graph representation of bacterial diversity can be used to identify species and resistance profiles of clinical isolates. We implement this method for Staphylococcus aureus and Mycobacterium tuberculosis in a software package ('Mykrobe predictor') that takes raw sequence data as input, and generates a clinician-friendly report within 3 minutes on a laptop. For S. aureus, the error rates of our method are comparable to gold-standard phenotypic methods, with sensitivity/specificity of 99.1%/99.6% across 12 antibiotics (using an independent validation set, n=470). For M. tuberculosis, our method predicts resistance with sensitivity/specificity of 82.6%/98.5% (independent validation set, n=1,609); sensitivity is lower here, probably because of limited understanding of the underlying genetic mechanisms. We give evidence that minor alleles improve detection of extremely drug-resistant strains, and demonstrate feasibility of the use of emerging single-molecule nanopore sequencing techniques for these purposes.

References

Oct 19, 1999·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·G LinaJ Etienne
Jun 19, 2002·Antimicrobial Agents and Chemotherapy·Laura J V PiddockMartin J Everett
Jan 22, 2004·Bioinformatics·Emmanuel ParadisKorbinian Strimmer
Mar 30, 2004·Antimicrobial Agents and Chemotherapy·Deneke H MariamDan I Andersson
Jul 1, 2006·Science·Sebastien GagneuxBrendan J M Bohannan
Jan 27, 2007·Genome Research·Daniel H HusonStephan C Schuster
Apr 10, 2008·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·M KaaseS G Gatermann
Jun 2, 2009·Briefings in Bioinformatics·Mihai Pop
Jun 10, 2009·Bioinformatics·Heng Li1000 Genome Project Data Processing Subgroup
Jul 7, 2009·Respiratory Medicine·Hee-Jung JunWon-Jung Koh
Sep 18, 2009·Journal of Clinical Microbiology·Armand Van DeunA Wright
Nov 13, 2009·Proceedings of the National Academy of Sciences of the United States of America·M Analise ZaunbrecherJames E Posey
Apr 30, 2010·The Journal of Antimicrobial Chemotherapy·Claudia PlinkeStefan Niemann
Oct 29, 2010·Genome Research·Gerton Lunter, Martin Goodson
Mar 12, 2011·The Journal of Antimicrobial Chemotherapy·María VillarEmilio Pérez-Trallero
Dec 6, 2011·The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union Against Tuberculosis and Lung Disease·D A WilliamsonJ T Freeman
Jan 11, 2012·Nature Genetics·Zamin IqbalGil McVean
Jan 24, 2012·The European Respiratory Journal·Paolo MiottoDaniela M Cirillo
Apr 21, 2012·APMIS : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica·Erja Chryssanthou, Kristian Angeby
Jun 13, 2012·Nature Methods·Nicola SegataCurtis Huttenhower
Aug 8, 2012·Nature Reviews. Genetics·Xavier DidelotDerrick Crook
Oct 26, 2012·The Journal of Antimicrobial Chemotherapy·R A HoweBSAC Working Party on Susceptibility Testing
Mar 8, 2013·Journal of Clinical Microbiology·Raquel de Abreu MaschmannMaria Lucia Rosa Rossetti
Jun 14, 2013·Journal of Clinical Microbiology·Armand Van DeunBouke C de Jong
Jul 11, 2013·The Journal of Antimicrobial Chemotherapy·Jennifer HoVitali Sintchencko
Jul 19, 2013·The New England Journal of Medicine·Claudio U KöserSharon J Peacock
Dec 20, 2013·Journal of Clinical Microbiology·Timothy C RodwellAntonino Catanzaro
Feb 7, 2014·Journal of Clinical Microbiology·N Claire GordonTanya Golubchik
Mar 7, 2014·Molecular Biology and Evolution·Frederic BertelsErik van Nimwegen
Apr 11, 2014·Genome Research·Maisem LaabeiRuth C Massey
May 3, 2014·Journal of Clinical Microbiology·Thomas A KohlStefan Niemann
May 24, 2014·Nature Communications·Richard G EverittDaniel J Wilson
Oct 2, 2014·The New England Journal of Medicine·Carl Nathan, Otto Cars
Oct 10, 2014·BMC Genomics·Andreas SteinerSebastien Gagneux
Nov 26, 2014·Genome Medicine·Michael InouyeKathryn E Holt
Jan 30, 2015·Journal of Clinical Microbiology·Antonina A VotintsevaDerrick Crook
Jun 28, 2015·The Lancet Infectious Diseases·Timothy WalkerModernizing Medical Microbiology (MMM) Informatics Group
Jul 30, 2015·The Journal of Antimicrobial Chemotherapy·Kim JudgeSharon J Peacock

Citations

Feb 26, 2016·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Theodore R Pak, Andrew Kasarskis
Mar 30, 2016·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·Virve KorhonenHanna Soini
Sep 15, 2016·Expert Review of Anti-infective Therapy·Stefano G GiulieriBenjamin P Howden
Jan 18, 2017·Expert Review of Molecular Diagnostics·W Michael DunneAlex van Belkum
Mar 24, 2016·BMC Medicine·Adam A WitneyPhilip D Butcher
Jun 15, 2016·Scientific Reports·James J DavisRick L Stevens
Apr 11, 2017·Nature Reviews. Microbiology·Terence S CroftsGautam Dantas
Jun 3, 2017·Annals of the New York Academy of Sciences·Julie JeukensRoger C Levesque
Jan 31, 2017·Annals of the New York Academy of Sciences·Anita C Schürch, Willem van Schaik
Dec 10, 2016·International Journal of Mycobacteriology·Christopher Jeanes, Justin O'Grady
Feb 6, 2017·American Journal of Infection Control·Sanchita DasMichael O Vernon
Feb 6, 2017·American Journal of Infection Control·Patrick TangLinda M Hoang
Mar 24, 2017·Bioinformatics·L SchaefferL Pachter
Nov 29, 2016·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·M J EllingtonN Woodford
Nov 23, 2016·Annals of the New York Academy of Sciences·Andrew G McArthur, Kara K Tsang
Dec 18, 2016·International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases·Ruth McNerneyMarco Schito
Dec 21, 2016·Annals of the New York Academy of Sciences·Jian-Qiang SuYong-Guan Zhu
May 5, 2017·Nucleic Acids Research·Cedric C LacznyAndreas Keller
Dec 23, 2016·Annals of the New York Academy of Sciences·Jennifer L Guthrie, Jennifer L Gardy
Jan 8, 2017·Nucleic Acids Research·Eric van der HelmMorten O A Sommer
Apr 23, 2016·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·P PhakuF Schaumburg
Sep 1, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Do-Hee KimBong-Jin Lee
Apr 1, 2018·Annals of the New York Academy of Sciences·Shawn E Hawken, Evan S Snitkin
Mar 20, 2018·Bioinformatics·Isaac TurnerGil McVean
Apr 17, 2018·Médecine sciences : M/S·Christophe AudebertSégolène Caboche
May 3, 2018·Expert Review of Anti-infective Therapy·Ruth McNerneyTaane G Clark
Jun 24, 2017·European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology·F Tagini, Gilbert Greub
Oct 11, 2017·Journal of Experimental Botany·Richard M Leggett, Matthew D Clark
Jun 8, 2018·Annals of the New York Academy of Sciences·Tatum D Mortimer, Yonatan H Grad
Mar 2, 2018·Clinical Microbiology Reviews·Mridu SinhaStephanie I Fraley
Jul 31, 2016·Applied and Environmental Microbiology·Madikay SenghoreMartin Antonio
Sep 1, 2017·Clinical Microbiology Reviews·Scott QuainooHeiman F L Wertheim
Aug 8, 2018·Antimicrobial Agents and Chemotherapy·Justin L KandlerJames E Posey
Mar 17, 2017·Journal of Clinical Microbiology·Robyn S Lee, Madhukar Pai
Apr 28, 2017·Journal of Clinical Microbiology·Amel Kévin Alame-EmaneHoward E Takiff
Aug 1, 2018·Antimicrobial Agents and Chemotherapy·Tomasz JagielskiJarosław Dziadek
Mar 10, 2017·Journal of Clinical Microbiology·Antonina A VotintsevaZamin Iqbal
Nov 22, 2018·Microbial Genomics·Anna JohnningErik Kristiansson
Jan 31, 2019·Microbial Genomics·Leonor Sánchez-Busó, Simon Harris
Feb 23, 2019·The Journal of Antimicrobial Chemotherapy·Maha R FarhatMegan Murray
Jan 29, 2019·Molecular Biology and Evolution·James StimsonCaroline Colijn
Nov 2, 2018·Journal of Clinical Microbiology·Michelle SuTimothy D Read
Mar 20, 2019·Nature Reviews. Genetics·Manish BoolchandaniGautam Dantas
Sep 23, 2017·Genome Biology·Alexa B R McIntyreChristopher E Mason
Oct 28, 2016·Nature Reviews. Disease Primers·Madhukar PaiMario Raviglione
Mar 16, 2019·The Journal of Infectious Diseases·Irving Cancino-MuñozIñaki Comas
Nov 28, 2017·Microbial Genomics·Martin HuntSimon Harris
Oct 25, 2017·Nature Reviews. Microbiology·William O C M CooksonMiriam F Moffatt
Jun 7, 2019·Clinical Pharmacology and Therapeutics·Kimberley V SukhumGautam Dantas
Jan 2, 2016·Science·Michael BaymRoy Kishony
Sep 5, 2019·Microbial Genomics·Nicola De Maio On Behalf Of The Rehab Consortium
Aug 12, 2017·Scientific Reports·Etienne RuppéJacques Schrenzel
May 16, 2018·Bioinformatics·Will P M Rowe, Martyn D Winn
Nov 30, 2018·Briefings in Bioinformatics·Feng-Xu WuGuang-Fu Yang
Jan 9, 2020·Microbial Genomics·Stefano G GiulieriDeborah Williamson
Sep 16, 2017·Current Opinion in Infectious Diseases·Nenad MacesicNicholas P Tatonetti
Mar 14, 2020·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Vijay SrinivasanNguyen T T Thuong
Aug 1, 2020·Microbial Genomics·Katharine S WalterJason R Andrews
May 27, 2020·Annual Review of Genomics and Human Genetics·Jordan M EizengaErik Garrison
Jun 18, 2016·Proteomics. Clinical Applications·Yannick Charretier, Jacques Schrenzel
Apr 7, 2017·Genome Biology and Evolution·Julie JeukensRoger C Levesque
Jan 22, 2017·The Journal of Antimicrobial Chemotherapy·Alice LeddaXavier Didelot
Dec 15, 2018·PLoS Computational Biology·Danesh MoradigaravandLeopold Parts
Sep 26, 2019·Frontiers in Public Health·Rene S HendriksenPatrick F McDermott
Mar 3, 2020·Frontiers in Microbiology·Leonardo G Panunzi
Sep 13, 2020·Clinical Chemistry·Eric M RansomCarey-Ann D Burnham
Jul 30, 2016·Microbial Biotechnology·Mark J Pallen
Jun 15, 2017·American Journal of Respiratory and Critical Care Medicine·John Z MetcalfeDavid M Engelthaler
Oct 3, 2017·Briefings in Bioinformatics·Dionysios A AntonopoulosHyunseung Yoo
Dec 31, 2018·BMC Infectious Diseases·Balig PanossianSima Tokajian
Mar 29, 2019·Antimicrobial Agents and Chemotherapy·G Terrance WalkerDaniel Sahm
Jun 27, 2019·Nature Reviews. Microbiology·Dan I AnderssonKarin Hjort
Jun 19, 2019·Nature Reviews. Microbiology·Conor J MeehanAnnelies Van Rie
Dec 19, 2019·Frontiers in Microbiology·Julie E HansenKarl Pedersen
Feb 23, 2020·International Journal of Molecular Sciences·Pieter-Jan Van CampAleksey Porollo
Mar 24, 2020·Nature Reviews. Microbiology·Nicole E WheelerBenjamin Jeffrey
May 28, 2020·MBio·Michelle R ScribnerVaughn S Cooper
Nov 28, 2018·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Yuankai ZhangXuehai Yan
May 17, 2017·Animal Health Research Reviews·Yrjo T GrohnVictoriya Volkova
Feb 6, 2019·Nature Biotechnology·Phelim BradleyZamin Iqbal
Jun 13, 2020·Frontiers in Microbiology·Pieter-Jan Van CampAleksey Porollo
Feb 23, 2019·Emerging Infectious Diseases·Samuel LipworthDick van Soolingen
Jun 20, 2020·Expert Opinion on Drug Discovery·Mateus Sá Magalhães SerafimVinícius Gonçalves Maltarollo
Oct 18, 2020·GigaScience·Magali JaillardPierre Mahé
Nov 17, 2020·Frontiers in Microbiology·Xuefei LiJiajian Zhou
Nov 27, 2020·Frontiers in Genetics·Madangchanok ImchenVasco Azevedo
Jan 14, 2019·Kolin PaulPrashant Sharma

Related Concepts

Bacteriocidal Agents
Fungus Drug Sensitivity Tests
Mycobacterium tuberculosis H37Rv
Staphylococcal Infections
Staphylococcus aureus
Tuberculosis
Genome, Bacterial
Drug Resistance, Multiple, Bacterial
Alleles
Antibiotics

Related Feeds

CRISPR & Staphylococcus

CRISPR-Cas system enables the editing of genes to create or correct mutations. Staphylococci are associated with life-threatening infections in hospitals, as well as the community. Here is the latest research on how CRISPR-Cas system can be used for treatment of Staphylococcal infections.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.