title: Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance.
abstract: Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance. In particular, the katG mutation encoding p.Ser315Thr, which confers resistance to isoniazid, overwhelmingly arose before mutations that conferred rifampicin resistance across all of the lineages, geographical regions and time periods. Therefore, molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of polymorphisms that occur before the emergence of multidrug resistance, particularly katG p.Ser315Thr, into molecular diagnostics should enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB.
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Abigail L
authors.identifier: http://orcid.org/0000-0002-3800-0714
authors.initials: AL
authors.lastname: Manson
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|KwaZulu-Natal Research Institute for TB and HIV (K-RITH), Durban, South Africa.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Keira A
authors.initials: KA
authors.lastname: Cohen
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0002-7205-7431
authors.initials: T
authors.lastname: Abeel
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Desjardins
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Derek T
authors.initials: DT
authors.lastname: Armstrong
authors.affiliation: National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.affiliation: Medical Research Council, TB Platform, Pretoria, South Africa.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Brand
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Sinéad B
authors.initials: SB
authors.lastname: Chapman
authors.affiliation: International Tuberculosis Research Center, Changwon and Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
authors.affiliation: Office of Cyber Infrastructure and Computational Biology, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Gabrielian
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: James
authors.initials: J
authors.lastname: Gomez
authors.affiliation: Clinical Hospital of Pneumology Leon Daniello, Cluj Napoca, Romania.
authors.forename: Andreea M
authors.initials: AM
authors.lastname: Jodals
authors.affiliation: Department of Medical Microbiology, Mycobacteriology Laboratory, Makerere University, Kampala, Uganda.
authors.forename: Moses
authors.initials: M
authors.lastname: Joloba
authors.affiliation: Public Health Agency of Sweden, Solna, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Jureen
authors.affiliation: International Tuberculosis Research Center, Changwon and Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Medical Research Council, TB Platform, Pretoria, South Africa.
authors.forename: Lesibana
authors.initials: L
authors.lastname: Malinga
authors.affiliation: University of Sciences, Techniques and Technologies of Bamako (USTTB), Bamako, Mali.
authors.forename: Mamoudou
authors.initials: M
authors.lastname: Maiga
authors.affiliation: Novasano Health and Science, New York, New York, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Nordenberg
authors.affiliation: Microbiology and Morphology Laboratory, Phthisiopneumology Institute, Chisinau, Moldova.
authors.forename: Ecaterina
authors.initials: E
authors.lastname: Noroc
authors.affiliation: Microbiology and Morphology Laboratory, Phthisiopneumology Institute, Chisinau, Moldova.
authors.forename: Elena
authors.initials: E
authors.lastname: Romancenco
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands.
authors.forename: Alex
authors.identifier: http://orcid.org/0000-0002-8453-8769
authors.initials: A
authors.lastname: Salazar
authors.affiliation: Department of Medical Microbiology, Mycobacteriology Laboratory, Makerere University, Kampala, Uganda.
authors.forename: Willy
authors.initials: W
authors.lastname: Ssengooba
authors.affiliation: Mycobacteriology Research Centre, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: A A
authors.initials: AA
authors.lastname: Velayati
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Winglee
authors.affiliation: Republican Research and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus.
authors.forename: Aksana
authors.initials: A
authors.lastname: Zalutskaya
authors.affiliation: National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Via
authors.affiliation: Department of Global Health and Social Medicine, Harvard Medical School, Division of Global Health Equity, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Gail H
authors.initials: GH
authors.lastname: Cassell
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Dorman
authors.affiliation: Section of Infectious Diseases, Boston Medical Center, Boston, Massachusetts, USA.
authors.forename: Jerrold
authors.initials: J
authors.lastname: Ellner
authors.affiliation: Mycobacteriology Research Centre, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Parissa
authors.initials: P
authors.lastname: Farnia
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Biomedical Engineering and Microbiology, Boston University, Boston, Massachusetts, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Galagan
authors.affiliation: Office of Cyber Infrastructure and Computational Biology, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Rosenthal
authors.affiliation: Microbiology and Morphology Laboratory, Phthisiopneumology Institute, Chisinau, Moldova.
authors.forename: Valeriu
authors.initials: V
authors.lastname: Crudu
authors.affiliation: Clinical Hospital of Pneumology Leon Daniello, Cluj Napoca, Romania.
authors.forename: Daniela
authors.initials: D
authors.lastname: Homorodean
authors.affiliation: National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Po-Ren
authors.initials: PR
authors.lastname: Hsueh
authors.affiliation: National Institute for Research in Tuberculosis, Chennai, India.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: KwaZulu-Natal Research Institute for TB and HIV (K-RITH), Durban, South Africa.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Pym
authors.affiliation: Republican Research and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus.
authors.forename: Alena
authors.initials: A
authors.lastname: Skrahina
authors.affiliation: National Institute for Research in Tuberculosis, Chennai, India.
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Medical Research Council, TB Platform, Pretoria, South Africa.
authors.forename: Martie
authors.initials: M
authors.lastname: Van der Walt
authors.affiliation: Rutgers-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: David
authors.initials: D
authors.lastname: Alland
authors.affiliation: KwaZulu-Natal Research Institute for TB and HIV (K-RITH), Durban, South Africa.|Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
authors.affiliation: Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Cohen
authors.affiliation: Public Health Agency of Sweden, Solna, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Hoffner
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Birren
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Ashlee M
authors.initials: AM
authors.lastname: Earl
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics; D002374:Catalase / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D023281:Genomics / Q000379:methods; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D012293:Rifampin / Q000627:therapeutic use; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; D007538:Isoniazid; D012293:Rifampin