Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal
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{"title"=>"Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal", "type"=>"journal", "authors"=>[{"first_name"=>"Keira A.", "last_name"=>"Cohen", "scopus_author_id"=>"55756770800"}, {"first_name"=>"Thomas", "last_name"=>"Abeel", "scopus_author_id"=>"18533730700"}, {"first_name"=>"Abigail", "last_name"=>"Manson McGuire", "scopus_author_id"=>"56888715700"}, {"first_name"=>"Christopher A.", "last_name"=>"Desjardins", "scopus_author_id"=>"55913102400"}, {"first_name"=>"Vanisha", "last_name"=>"Munsamy", "scopus_author_id"=>"54389840700"}, {"first_name"=>"Terrance P.", "last_name"=>"Shea", "scopus_author_id"=>"7103034188"}, {"first_name"=>"Bruce J.", "last_name"=>"Walker", "scopus_author_id"=>"55024091600"}, {"first_name"=>"Nonkqubela", "last_name"=>"Bantubani", "scopus_author_id"=>"55220015500"}, {"first_name"=>"Deepak V.", "last_name"=>"Almeida", "scopus_author_id"=>"14059462100"}, {"first_name"=>"Lucia", "last_name"=>"Alvarado", "scopus_author_id"=>"26648029200"}, {"first_name"=>"Sinéad B.", "last_name"=>"Chapman", "scopus_author_id"=>"57200400577"}, {"first_name"=>"Nomonde R.", "last_name"=>"Mvelase", "scopus_author_id"=>"56486152600"}, {"first_name"=>"Eamon Y.", "last_name"=>"Duffy", "scopus_author_id"=>"56485434800"}, {"first_name"=>"Michael G.", "last_name"=>"Fitzgerald", "scopus_author_id"=>"8947605600"}, {"first_name"=>"Pamla", "last_name"=>"Govender", "scopus_author_id"=>"49863143200"}, {"first_name"=>"Sharvari", "last_name"=>"Gujja", "scopus_author_id"=>"36094067900"}, {"first_name"=>"Susanna", "last_name"=>"Hamilton", "scopus_author_id"=>"56485141700"}, {"first_name"=>"Clinton", "last_name"=>"Howarth", "scopus_author_id"=>"26648493700"}, {"first_name"=>"Jeffrey D.", "last_name"=>"Larimer", "scopus_author_id"=>"56485484400"}, {"first_name"=>"Kashmeel", "last_name"=>"Maharaj", "scopus_author_id"=>"6603638335"}, {"first_name"=>"Matthew D.", "last_name"=>"Pearson", "scopus_author_id"=>"16029635900"}, {"first_name"=>"Margaret E.", "last_name"=>"Priest", "scopus_author_id"=>"16310838200"}, {"first_name"=>"Qiandong", "last_name"=>"Zeng", "scopus_author_id"=>"8947609300"}, {"first_name"=>"Nesri", "last_name"=>"Padayatchi", "scopus_author_id"=>"6603387290"}, {"first_name"=>"Jacques", "last_name"=>"Grosset", "scopus_author_id"=>"7101698082"}, {"first_name"=>"Sarah K.", "last_name"=>"Young", "scopus_author_id"=>"56888234000"}, {"first_name"=>"Jennifer", "last_name"=>"Wortman", "scopus_author_id"=>"7006948361"}, {"first_name"=>"Koleka P.", "last_name"=>"Mlisana", "scopus_author_id"=>"14050735400"}, {"first_name"=>"Max R.", "last_name"=>"O'Donnell", "scopus_author_id"=>"7402328944"}, {"first_name"=>"Bruce W.", "last_name"=>"Birren", "scopus_author_id"=>"7003582624"}, {"first_name"=>"William R.", "last_name"=>"Bishai", "scopus_author_id"=>"7005156752"}, {"first_name"=>"Alexander S.", "last_name"=>"Pym", "scopus_author_id"=>"57200265521"}, {"first_name"=>"Ashlee M.", "last_name"=>"Earl", "scopus_author_id"=>"6701634699"}], "year"=>2015, "source"=>"PLoS Medicine", "identifiers"=>{"issn"=>"15491676", "scopus"=>"2-s2.0-84943151497", "pui"=>"606283754", "doi"=>"10.1371/journal.pmed.1001880", "isbn"=>"1549-1676; 1549-1277", "sgr"=>"84943151497", "pmid"=>"26418737"}, "id"=>"b20836dd-96f7-3342-a82f-9e233cb3787c", "abstract"=>"BACKGROUND: The continued advance of antibiotic resistance threatens the treatment and control of many infectious diseases. This is exemplified by the largest global outbreak of extensively drug-resistant (XDR) tuberculosis (TB) identified in Tugela Ferry, KwaZulu-Natal, South Africa, in 2005 that continues today. It is unclear whether the emergence of XDR-TB in KwaZulu-Natal was due to recent inadequacies in TB control in conjunction with HIV or other factors. Understanding the origins of drug resistance in this fatal outbreak of XDR will inform the control and prevention of drug-resistant TB in other settings. In this study, we used whole genome sequencing and dating analysis to determine if XDR-TB had emerged recently or had ancient antecedents.\\n\\nMETHODS AND FINDINGS: We performed whole genome sequencing and drug susceptibility testing on 337 clinical isolates of Mycobacterium tuberculosis collected in KwaZulu-Natal from 2008 to 2013, in addition to three historical isolates, collected from patients in the same province and including an isolate from the 2005 Tugela Ferry XDR outbreak, a multidrug-resistant (MDR) isolate from 1994, and a pansusceptible isolate from 1995. We utilized an array of whole genome comparative techniques to assess the relatedness among strains, to establish the order of acquisition of drug resistance mutations, including the timing of acquisitions leading to XDR-TB in the LAM4 spoligotype, and to calculate the number of independent evolutionary emergences of MDR and XDR. Our sequencing and analysis revealed a 50-member clone of XDR M. tuberculosis that was highly related to the Tugela Ferry XDR outbreak strain. We estimated that mutations conferring isoniazid and streptomycin resistance in this clone were acquired 50 y prior to the Tugela Ferry outbreak (katG S315T [isoniazid]; gidB 130 bp deletion [streptomycin]; 1957 [95% highest posterior density (HPD): 1937-1971]), with the subsequent emergence of MDR and XDR occurring 20 y (rpoB L452P [rifampicin]; pncA 1 bp insertion [pyrazinamide]; 1984 [95% HPD: 1974-1992]) and 10 y (rpoB D435G [rifampicin]; rrs 1400 [kanamycin]; gyrA A90V [ofloxacin]; 1995 [95% HPD: 1988-1999]) prior to the outbreak, respectively. We observed frequent de novo evolution of MDR and XDR, with 56 and nine independent evolutionary events, respectively. Isoniazid resistance evolved before rifampicin resistance 46 times, whereas rifampicin resistance evolved prior to isoniazid only twice. We identified additional putative compensatory mutations to rifampicin in this dataset. One major limitation of this study is that the conclusions with respect to ordering and timing of acquisition of mutations may not represent universal patterns of drug resistance emergence in other areas of the globe.\\n\\nCONCLUSIONS: In the first whole genome-based analysis of the emergence of drug resistance among clinical isolates of M. tuberculosis, we show that the ancestral precursor of the LAM4 XDR outbreak strain in Tugela Ferry gained mutations to first-line drugs at the beginning of the antibiotic era. Subsequent accumulation of stepwise resistance mutations, occurring over decades and prior to the explosion of HIV in this region, yielded MDR and XDR, permitting the emergence of compensatory mutations. Our results suggest that drug-resistant strains circulating today reflect not only vulnerabilities of current TB control efforts but also those that date back 50 y. In drug-resistant TB, isoniazid resistance was overwhelmingly the initial resistance mutation to be acquired, which would not be detected by current rapid molecular diagnostics employed in South Africa that assess only rifampicin resistance.", "link"=>"http://www.mendeley.com/research/evolution-extensively-drugresistant-tuberculosis-four-decades-whole-genome-sequencing-dating-analysi", "reader_count"=>222, "reader_count_by_academic_status"=>{"Unspecified"=>12, "Professor > Associate Professor"=>5, "Librarian"=>1, "Researcher"=>49, "Student > Doctoral Student"=>13, "Student > Ph. D. Student"=>38, "Student > Postgraduate"=>13, "Student > Master"=>44, "Other"=>11, "Student > Bachelor"=>21, "Lecturer"=>6, "Lecturer > Senior Lecturer"=>4, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>12, "Professor > Associate Professor"=>5, "Librarian"=>1, "Researcher"=>49, "Student > Doctoral Student"=>13, "Student > Ph. D. Student"=>38, "Student > Postgraduate"=>13, "Student > Master"=>44, "Other"=>11, "Student > Bachelor"=>21, "Lecturer"=>6, "Lecturer > Senior Lecturer"=>4, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>22, "Agricultural and Biological Sciences"=>57, "Chemical Engineering"=>2, "Chemistry"=>2, "Computer Science"=>7, "Economics, Econometrics and Finance"=>1, "Engineering"=>1, "Environmental Science"=>2, "Biochemistry, Genetics and Molecular Biology"=>48, "Nursing and Health Professions"=>3, "Mathematics"=>2, "Medicine and Dentistry"=>50, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Social Sciences"=>5, "Immunology and Microbiology"=>17, "Linguistics"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>50}, "Social Sciences"=>{"Social Sciences"=>5}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>22}, "Environmental Science"=>{"Environmental Science"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}, "Chemical Engineering"=>{"Chemical Engineering"=>2}, "Engineering"=>{"Engineering"=>1}, "Chemistry"=>{"Chemistry"=>2}, "Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>17}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>57}, "Computer Science"=>{"Computer Science"=>7}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>3}, "Linguistics"=>{"Linguistics"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>48}}, "reader_count_by_country"=>{"Netherlands"=>2, "United States"=>2, "South Africa"=>1, "United Kingdom"=>1, "Mexico"=>1, "Spain"=>1, "India"=>1}, "group_count"=>6}

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  • {"files"=>["https://ndownloader.figshare.com/files/2292651"], "description"=>"<p>* HIV-positive and HIV-negative individuals were compared using Fisher’s exact test for categorical variables and nonparametric Mann-Whitney test for continuous variables.</p><p><sup>†</sup> Data in this row are from the XDR data, not the total dataset.</p><p>Results having a <i>p</i>-value < 0.05 were considered statistically significant.</p><p>Data are <i>n</i> (%) or mean ± standard deviation (SD).</p>", "links"=>[], "tags"=>["Tugela Ferry outbreak", "Genome sequencing", "drug resistance emergence", "katG S 315T", "50 y", "Tugela Ferry XDR outbreak strain", "Whole Genome Sequencing", "drug resistance mutations", "rpoB L 452P", "rifampicin resistance 46 times", "rifampicin resistance", "LAM 4 spoligotype", "Tugela Ferry", "TB control efforts", "90V", "Mycobacterium tuberculosis Isolates", "LAM 4 XDR outbreak strain", "mdr", "rpoB D 435G", "2005 Tugela Ferry XDR outbreak", "Drug Resistance", "hiv", "hpd", "drug susceptibility testing"], "article_id"=>1559501, "categories"=>["Uncategorised"], "users"=>["Keira A. Cohen", "Thomas Abeel", "Abigail Manson McGuire", "Christopher A. Desjardins", "Vanisha Munsamy", "Terrance P. Shea", "Bruce J. Walker", "Nonkqubela Bantubani", "Deepak V. Almeida", "Lucia Alvarado", "Sinéad B. Chapman", "Nomonde R. Mvelase", "Eamon Y. Duffy", "Michael G. FitzGerald", "Pamla Govender", "Sharvari Gujja", "Susanna Hamilton", "Clinton Howarth", "Jeffrey D. Larimer", "Kashmeel Maharaj", "Matthew D. Pearson", "Margaret E. Priest", "Qiandong Zeng", "Nesri Padayatchi", "Jacques Grosset", "Sarah K. Young", "Jennifer Wortman", "Koleka P. Mlisana", "Max R. O'Donnell", "Bruce W. Birren", "William R. Bishai", "Alexander S. Pym", "Ashlee M. Earl"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001880.t002", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Demographic_characteristics_of_participants_and_phenotypic_drug_susceptibility_of_strains_/1559501", "title"=>"Demographic characteristics of participants and phenotypic drug susceptibility of strains.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-09-29 03:20:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2292650"], "description"=>"<p>The 337 clinical study isolates derived from five patient cohorts and were both prospectively and retrospectively collected from all 11 districts of KwaZulu-Natal from 2008 to 2013. Culture conditions describe the initial <i>M</i>. <i>tuberculosis</i> isolation method from sputum. If subsequent single colony isolation (SCI) was performed prior to DNA extraction on the entire study cohort or a subset of the cohort, then this is denoted. Drugs for which DST was performed are abbreviated as follows: rifampicin (R), isoniazid (H), nicotinamide (N), pyrazinamide (P), ethambutol (E), streptomycin (S), kanamycin (K), ofloxacin (O), ethionamide (Et), and capreomycin (C).</p>", "links"=>[], "tags"=>["Tugela Ferry outbreak", "Genome sequencing", "drug resistance emergence", "katG S 315T", "50 y", "Tugela Ferry XDR outbreak strain", "Whole Genome Sequencing", "drug resistance mutations", "rpoB L 452P", "rifampicin resistance 46 times", "rifampicin resistance", "LAM 4 spoligotype", "Tugela Ferry", "TB control efforts", "90V", "Mycobacterium tuberculosis Isolates", "LAM 4 XDR outbreak strain", "mdr", "rpoB D 435G", "2005 Tugela Ferry XDR outbreak", "Drug Resistance", "hiv", "hpd", "drug susceptibility testing"], "article_id"=>1559500, "categories"=>["Uncategorised"], "users"=>["Keira A. Cohen", "Thomas Abeel", "Abigail Manson McGuire", "Christopher A. Desjardins", "Vanisha Munsamy", "Terrance P. Shea", "Bruce J. Walker", "Nonkqubela Bantubani", "Deepak V. Almeida", "Lucia Alvarado", "Sinéad B. Chapman", "Nomonde R. Mvelase", "Eamon Y. Duffy", "Michael G. FitzGerald", "Pamla Govender", "Sharvari Gujja", "Susanna Hamilton", "Clinton Howarth", "Jeffrey D. Larimer", "Kashmeel Maharaj", "Matthew D. Pearson", "Margaret E. Priest", "Qiandong Zeng", "Nesri Padayatchi", "Jacques Grosset", "Sarah K. Young", "Jennifer Wortman", "Koleka P. Mlisana", "Max R. O'Donnell", "Bruce W. Birren", "William R. Bishai", "Alexander S. Pym", "Ashlee M. Earl"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001880.t001", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Description_of_study_isolates_/1559500", "title"=>"Description of study isolates.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-09-29 03:20:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2292647"], "description"=>"<p>A map of the 11 districts of KwaZulu-Natal [<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001880#pmed.1001880.ref052\" target=\"_blank\">52</a>] is shown in which pie charts indicate (A) the fraction of sequenced <i>M</i>. <i>tuberculosis</i> belonging to computationally predicted spoligotypes (see key). In (B), the fraction of strains with a phenotypic classification of XDR and membership in the Tugela Ferry XDR Clone are represented (see key). The size of the pie chart indicates the relative number of strains sequenced from each of the 11 districts within KwaZulu Natal. Tugela Ferry, in the uMzinyathi district, is indicated in red.</p>", "links"=>[], "tags"=>["Tugela Ferry outbreak", "Genome sequencing", "drug resistance emergence", "katG S 315T", "50 y", "Tugela Ferry XDR outbreak strain", "Whole Genome Sequencing", "drug resistance mutations", "rpoB L 452P", "rifampicin resistance 46 times", "rifampicin resistance", "LAM 4 spoligotype", "Tugela Ferry", "TB control efforts", "90V", "Mycobacterium tuberculosis Isolates", "LAM 4 XDR outbreak strain", "mdr", "rpoB D 435G", "2005 Tugela Ferry XDR outbreak", "Drug Resistance", "hiv", "hpd", "drug susceptibility testing"], "article_id"=>1559497, "categories"=>["Uncategorised"], "users"=>["Keira A. Cohen", "Thomas Abeel", "Abigail Manson McGuire", "Christopher A. Desjardins", "Vanisha Munsamy", "Terrance P. Shea", "Bruce J. Walker", "Nonkqubela Bantubani", "Deepak V. Almeida", "Lucia Alvarado", "Sinéad B. Chapman", "Nomonde R. Mvelase", "Eamon Y. Duffy", "Michael G. FitzGerald", "Pamla Govender", "Sharvari Gujja", "Susanna Hamilton", "Clinton Howarth", "Jeffrey D. Larimer", "Kashmeel Maharaj", "Matthew D. Pearson", "Margaret E. Priest", "Qiandong Zeng", "Nesri Padayatchi", "Jacques Grosset", "Sarah K. Young", "Jennifer Wortman", "Koleka P. Mlisana", "Max R. O'Donnell", "Bruce W. Birren", "William R. Bishai", "Alexander S. Pym", "Ashlee M. Earl"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001880.g002", "stats"=>{"downloads"=>2, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Wide_geographic_spread_of_diverse_strains_across_KwaZulu_Natal_and_wide_distribution_of_XDR_and_the_Tugela_Ferry_XDR_Clone_members_/1559497", "title"=>"Wide geographic spread of diverse strains across KwaZulu-Natal and wide distribution of XDR and the Tugela Ferry XDR Clone members.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-29 03:20:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2292646"], "description"=>"<p>(A) Midpoint rooted maximum-likelihood phylogeny of 340 <i>M</i>. <i>tuberculosis</i> isolates. Four of the seven known <i>M</i>. <i>tuberculosis</i> lineages were identified: CAS (<i>Lin1</i>), Beijing (<i>Lin2</i>), EAI (<i>Lin 3</i>), and Euro-American (<i>Lin4</i>). Digital spoligotyping identified 17 unique spoligotypes in the dataset; spoligotypes are shown on this figure if they are represented by three or more strains. Corresponding spoligotypes and phenotypes are reported for all strains in <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001880#pmed.1001880.s009\" target=\"_blank\">S4 Table</a>. Phenotypic XDR, MDR, poly- and monodrug resistance (labeled “Drug-resistant other”), and pansusceptible strains are indicated by colored tick marks at the tip of each leaf node. (B) Histogram of pairwise SNP distances between strains. The number of pairs within each SNP distance range is plotted. The peaks correspond to the distance between major lineages. The peak at the far left of the figure corresponds to the distance between pairs of strains within a clone.</p>", "links"=>[], "tags"=>["Tugela Ferry outbreak", "Genome sequencing", "drug resistance emergence", "katG S 315T", "50 y", "Tugela Ferry XDR outbreak strain", "Whole Genome Sequencing", "drug resistance mutations", "rpoB L 452P", "rifampicin resistance 46 times", "rifampicin resistance", "LAM 4 spoligotype", "Tugela Ferry", "TB control efforts", "90V", "Mycobacterium tuberculosis Isolates", "LAM 4 XDR outbreak strain", "mdr", "rpoB D 435G", "2005 Tugela Ferry XDR outbreak", "Drug Resistance", "hiv", "hpd", "drug susceptibility testing"], "article_id"=>1559496, "categories"=>["Uncategorised"], "users"=>["Keira A. Cohen", "Thomas Abeel", "Abigail Manson McGuire", "Christopher A. Desjardins", "Vanisha Munsamy", "Terrance P. Shea", "Bruce J. Walker", "Nonkqubela Bantubani", "Deepak V. Almeida", "Lucia Alvarado", "Sinéad B. Chapman", "Nomonde R. Mvelase", "Eamon Y. Duffy", "Michael G. FitzGerald", "Pamla Govender", "Sharvari Gujja", "Susanna Hamilton", "Clinton Howarth", "Jeffrey D. Larimer", "Kashmeel Maharaj", "Matthew D. Pearson", "Margaret E. Priest", "Qiandong Zeng", "Nesri Padayatchi", "Jacques Grosset", "Sarah K. Young", "Jennifer Wortman", "Koleka P. Mlisana", "Max R. O'Donnell", "Bruce W. Birren", "William R. Bishai", "Alexander S. Pym", "Ashlee M. Earl"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001880.g001", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Diverse_strains_contribute_to_drug_resistance_in_KwaZulu_Natal_/1559496", "title"=>"Diverse strains contribute to drug resistance in KwaZulu-Natal.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-29 03:20:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2292661", "https://ndownloader.figshare.com/files/2292662", "https://ndownloader.figshare.com/files/2292663", "https://ndownloader.figshare.com/files/2292664", "https://ndownloader.figshare.com/files/2292665", "https://ndownloader.figshare.com/files/2292666", "https://ndownloader.figshare.com/files/2292667", "https://ndownloader.figshare.com/files/2292668", "https://ndownloader.figshare.com/files/2292669", "https://ndownloader.figshare.com/files/2292670", "https://ndownloader.figshare.com/files/2292671"], "description"=>"<div><p>Background</p><p>The continued advance of antibiotic resistance threatens the treatment and control of many infectious diseases. This is exemplified by the largest global outbreak of extensively drug-resistant (XDR) tuberculosis (TB) identified in Tugela Ferry, KwaZulu-Natal, South Africa, in 2005 that continues today. It is unclear whether the emergence of XDR-TB in KwaZulu-Natal was due to recent inadequacies in TB control in conjunction with HIV or other factors. Understanding the origins of drug resistance in this fatal outbreak of XDR will inform the control and prevention of drug-resistant TB in other settings. In this study, we used whole genome sequencing and dating analysis to determine if XDR-TB had emerged recently or had ancient antecedents.</p><p>Methods and Findings</p><p>We performed whole genome sequencing and drug susceptibility testing on 337 clinical isolates of <i>Mycobacterium tuberculosis</i> collected in KwaZulu-Natal from 2008 to 2013, in addition to three historical isolates, collected from patients in the same province and including an isolate from the 2005 Tugela Ferry XDR outbreak, a multidrug-resistant (MDR) isolate from 1994, and a pansusceptible isolate from 1995. We utilized an array of whole genome comparative techniques to assess the relatedness among strains, to establish the order of acquisition of drug resistance mutations, including the timing of acquisitions leading to XDR-TB in the LAM4 spoligotype, and to calculate the number of independent evolutionary emergences of MDR and XDR. Our sequencing and analysis revealed a 50-member clone of XDR <i>M</i>. <i>tuberculosis</i> that was highly related to the Tugela Ferry XDR outbreak strain. We estimated that mutations conferring isoniazid and streptomycin resistance in this clone were acquired 50 y prior to the Tugela Ferry outbreak (<i>katG</i> S315T [isoniazid]; <i>gidB</i> 130 bp deletion [streptomycin]; 1957 [95% highest posterior density (HPD): 1937–1971]), with the subsequent emergence of MDR and XDR occurring 20 y (<i>rpoB</i> L452P [rifampicin]; <i>pncA</i> 1 bp insertion [pyrazinamide]; 1984 [95% HPD: 1974–1992]) and 10 y (<i>rpoB</i> D435G [rifampicin]; <i>rrs</i> 1400 [kanamycin]; <i>gyrA</i> A90V [ofloxacin]; 1995 [95% HPD: 1988–1999]) prior to the outbreak, respectively. We observed frequent de novo evolution of MDR and XDR, with 56 and nine independent evolutionary events, respectively. Isoniazid resistance evolved before rifampicin resistance 46 times, whereas rifampicin resistance evolved prior to isoniazid only twice. We identified additional putative compensatory mutations to rifampicin in this dataset. One major limitation of this study is that the conclusions with respect to ordering and timing of acquisition of mutations may not represent universal patterns of drug resistance emergence in other areas of the globe.</p><p>Conclusions</p><p>In the first whole genome-based analysis of the emergence of drug resistance among clinical isolates of <i>M</i>. <i>tuberculosis</i>, we show that the ancestral precursor of the LAM4 XDR outbreak strain in Tugela Ferry gained mutations to first-line drugs at the beginning of the antibiotic era. Subsequent accumulation of stepwise resistance mutations, occurring over decades and prior to the explosion of HIV in this region, yielded MDR and XDR, permitting the emergence of compensatory mutations. Our results suggest that drug-resistant strains circulating today reflect not only vulnerabilities of current TB control efforts but also those that date back 50 y. In drug-resistant TB, isoniazid resistance was overwhelmingly the initial resistance mutation to be acquired, which would not be detected by current rapid molecular diagnostics employed in South Africa that assess only rifampicin resistance.</p></div>", "links"=>[], "tags"=>["Tugela Ferry outbreak", "Genome sequencing", "drug resistance emergence", "katG S 315T", "50 y", "Tugela Ferry XDR outbreak strain", "Whole Genome Sequencing", "drug resistance mutations", "rpoB L 452P", "rifampicin resistance 46 times", "rifampicin resistance", "LAM 4 spoligotype", "Tugela Ferry", "TB control efforts", "90V", "Mycobacterium tuberculosis Isolates", "LAM 4 XDR outbreak strain", "mdr", "rpoB D 435G", "2005 Tugela Ferry XDR outbreak", "Drug Resistance", "hiv", "hpd", "drug susceptibility testing"], "article_id"=>1559504, "categories"=>["Uncategorised"], "users"=>["Keira A. Cohen", "Thomas Abeel", "Abigail Manson McGuire", "Christopher A. Desjardins", "Vanisha Munsamy", "Terrance P. Shea", "Bruce J. Walker", "Nonkqubela Bantubani", "Deepak V. Almeida", "Lucia Alvarado", "Sinéad B. Chapman", "Nomonde R. Mvelase", "Eamon Y. Duffy", "Michael G. FitzGerald", "Pamla Govender", "Sharvari Gujja", "Susanna Hamilton", "Clinton Howarth", "Jeffrey D. Larimer", "Kashmeel Maharaj", "Matthew D. Pearson", "Margaret E. Priest", "Qiandong Zeng", "Nesri Padayatchi", "Jacques Grosset", "Sarah K. Young", "Jennifer Wortman", "Koleka P. Mlisana", "Max R. O'Donnell", "Bruce W. Birren", "William R. Bishai", "Alexander S. Pym", "Ashlee M. Earl"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001880.s001", "https://dx.doi.org/10.1371/journal.pmed.1001880.s002", "https://dx.doi.org/10.1371/journal.pmed.1001880.s003", "https://dx.doi.org/10.1371/journal.pmed.1001880.s004", "https://dx.doi.org/10.1371/journal.pmed.1001880.s005", "https://dx.doi.org/10.1371/journal.pmed.1001880.s006", "https://dx.doi.org/10.1371/journal.pmed.1001880.s007", "https://dx.doi.org/10.1371/journal.pmed.1001880.s008", "https://dx.doi.org/10.1371/journal.pmed.1001880.s009", "https://dx.doi.org/10.1371/journal.pmed.1001880.s010", "https://dx.doi.org/10.1371/journal.pmed.1001880.s011"], "stats"=>{"downloads"=>13, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Evolution_of_Extensively_Drug_Resistant_Tuberculosis_over_Four_Decades_Whole_Genome_Sequencing_and_Dating_Analysis_of_Mycobacterium_tuberculosis_Isolates_from_KwaZulu_Natal/1559504", "title"=>"Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of <i>Mycobacterium tuberculosis</i> Isolates from KwaZulu-Natal", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-09-29 03:20:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2292649"], "description"=>"<p>Acquisition of <i>katG</i> S315 mutations precedes all other resistance mutations, including rifampicin, in all instances in which the order of acquisition can be disambiguated. For the 214 strains with genotypic resistance to two or more MDR or XDR defining drugs, and in which the order of acquisition of these mutations could be disambiguated, we quantified the number of evolutions in which resistance to one drug was gained before resistance to a second drug. Isoniazid resistance was divided into mutations conferred by the <i>katG</i>S315 codon versus “Other INH” mutations (defined as loss-of-function mutations in <i>katG</i> that do not involve codon 315 or mutations in the <i>inhA</i> promoter). Reported numbers represent the number of independent evolutionary events (not the number of strains) in which the drug resistance indicated by the row labeled “first resistance” was acquired before the drug resistance indicated by the column labeled “second resistance.” The background color is shaded to indicate the fraction of unambiguous evolutionary events in which the “first resistance” was acquired before the “second resistance” for that given drug pair.</p>", "links"=>[], "tags"=>["Tugela Ferry outbreak", "Genome sequencing", "drug resistance emergence", "katG S 315T", "50 y", "Tugela Ferry XDR outbreak strain", "Whole Genome Sequencing", "drug resistance mutations", "rpoB L 452P", "rifampicin resistance 46 times", "rifampicin resistance", "LAM 4 spoligotype", "Tugela Ferry", "TB control efforts", "90V", "Mycobacterium tuberculosis Isolates", "LAM 4 XDR outbreak strain", "mdr", "rpoB D 435G", "2005 Tugela Ferry XDR outbreak", "Drug Resistance", "hiv", "hpd", "drug susceptibility testing"], "article_id"=>1559499, "categories"=>["Uncategorised"], "users"=>["Keira A. Cohen", "Thomas Abeel", "Abigail Manson McGuire", "Christopher A. Desjardins", "Vanisha Munsamy", "Terrance P. Shea", "Bruce J. Walker", "Nonkqubela Bantubani", "Deepak V. Almeida", "Lucia Alvarado", "Sinéad B. Chapman", "Nomonde R. Mvelase", "Eamon Y. Duffy", "Michael G. FitzGerald", "Pamla Govender", "Sharvari Gujja", "Susanna Hamilton", "Clinton Howarth", "Jeffrey D. Larimer", "Kashmeel Maharaj", "Matthew D. Pearson", "Margaret E. Priest", "Qiandong Zeng", "Nesri Padayatchi", "Jacques Grosset", "Sarah K. Young", "Jennifer Wortman", "Koleka P. Mlisana", "Max R. O'Donnell", "Bruce W. Birren", "William R. Bishai", "Alexander S. Pym", "Ashlee M. Earl"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001880.g004", "stats"=>{"downloads"=>1, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Isoniazid_resistance_is_the_first_step_towards_drug_resistance_/1559499", "title"=>"Isoniazid resistance is the first step towards drug resistance.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-29 03:20:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2292648"], "description"=>"<p>Midpoint rooted maximum-likelihood phylogeny of 107 <i>M</i>. <i>tuberculosis</i> isolates of the LAM4 spoligotype. The gray shaded box identifies the Tugela Ferry XDR Clone. KZN605, the historical XDR strain collected in Tugela Ferry during the outbreak, is a member of this clone. Two additional historical isolates, KZN1435 and KZN4207, are not members of the Tugela Ferry XDR Clone. Each evolutionary gain of a drug resistance mutation was assigned to its position on the phylogenetic tree by parsimony (colored circles). A–E traces the stepwise order of drug resistance acquisition in the Tugela Ferry XDR Clone and estimates the year when each mutation was gained. Gray bars indicate the 95% highest posterior density (HPD) intervals. (A) <i>katG</i> S315T (isoniazid); <i>gidB</i> 130 bp deletion (streptomycin); 1957 (95% HPD: 1937–1971); (B) <i>inhA</i> promoter -8 (isoniazid and ethionamide); 1964 (95% HPD: 1948–1976); (C) <i>embB</i> M306V (ethambutol); 1967 (95% HPD: 1950–1978); (D) <i>rpoB</i> L452P (rifampicin); <i>pncA</i> 1bp insertion (pyrazinamide); 1984 (95% HPD: 1974–1992); and (E) <i>rpoB</i> D435G (rifampicin); <i>rrs</i> 1400 (kanamycin); <i>gyrA</i> A90V (ofloxacin); 1995 (95% HPD: 1988–1999). The accumulation of individual drug-resistant mutations within a strain is denoted to the right of the phylogenetic tree. The dates of drug discovery are displayed at the bottom of the figure [<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001880#pmed.1001880.ref053\" target=\"_blank\">53</a>]. Four additional LAM4 strains on a distant branch were not included in this figure because of size constraints. Bootstrap values are provided for lettered nodes, and bootstrap values for all nodes are shown in S5 Fig.</p>", "links"=>[], "tags"=>["Tugela Ferry outbreak", "Genome sequencing", "drug resistance emergence", "katG S 315T", "50 y", "Tugela Ferry XDR outbreak strain", "Whole Genome Sequencing", "drug resistance mutations", "rpoB L 452P", "rifampicin resistance 46 times", "rifampicin resistance", "LAM 4 spoligotype", "Tugela Ferry", "TB control efforts", "90V", "Mycobacterium tuberculosis Isolates", "LAM 4 XDR outbreak strain", "mdr", "rpoB D 435G", "2005 Tugela Ferry XDR outbreak", "Drug Resistance", "hiv", "hpd", "drug susceptibility testing"], "article_id"=>1559498, "categories"=>["Uncategorised"], "users"=>["Keira A. Cohen", "Thomas Abeel", "Abigail Manson McGuire", "Christopher A. Desjardins", "Vanisha Munsamy", "Terrance P. Shea", "Bruce J. Walker", "Nonkqubela Bantubani", "Deepak V. Almeida", "Lucia Alvarado", "Sinéad B. Chapman", "Nomonde R. Mvelase", "Eamon Y. Duffy", "Michael G. FitzGerald", "Pamla Govender", "Sharvari Gujja", "Susanna Hamilton", "Clinton Howarth", "Jeffrey D. Larimer", "Kashmeel Maharaj", "Matthew D. Pearson", "Margaret E. Priest", "Qiandong Zeng", "Nesri Padayatchi", "Jacques Grosset", "Sarah K. Young", "Jennifer Wortman", "Koleka P. Mlisana", "Max R. O'Donnell", "Bruce W. Birren", "William R. Bishai", "Alexander S. Pym", "Ashlee M. Earl"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001880.g003", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Molecular_evolution_and_dating_of_drug_resistance_emergence_within_the_Tugela_Ferry_XDR_Clone_/1559498", "title"=>"Molecular evolution and dating of drug resistance emergence within the Tugela Ferry XDR Clone.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-29 03:20:38"}

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{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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