Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance

TBResist Global Genome Consortium, Abigail L. Manson, Keira A. Cohen, Thomas Abeel, Christopher A. Desjardins, Derek T. Armstrong, Clifton E. Barry, Jeannette Brand, Sinéad B. Chapman, Sang Nae Cho, Andrei Gabrielian, James Gomez, Andreea M. Jodals, Moses Joloba, Pontus Jureen, Jong Seok Lee, Lesibana Malinga, Mamoudou Maiga, Dale Nordenberg, Ecaterina Noroc & 27 others Elena Romancenco, Alex Salazar, Willy Ssengooba, A. A. Velayati, Kathryn Winglee, Aksana Zalutskaya, Laura E. Via, Gail H. Cassell, Jerrold Ellner, Parissa Farnia, Parissa Farnia, James E. Galagan, Alex Rosenthal, Valeriu Crudu, Daniela Homorodean, Po Ren Hsueh, Sujatha Narayanan, Alexander S. Pym, Alena Skrahina, Soumya Swaminathan, Martie van der Walt, David Alland, William R. Bishai, Ted Cohen, Sven Hoffner, Bruce W. Birren, Ashlee M. Earl

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
JournalNature Genetics
DOIs
StateAccepted/In press - Jan 16 2017

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Multidrug-Resistant Tuberculosis
Multiple Drug Resistance
Mycobacterium tuberculosis
Molecular Pathology
Rifampin
Drug Resistance
Mutation
Isoniazid
Genome
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Genetics

Cite this

Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance. / TBResist Global Genome Consortium; Ellner, Jerrold; Farnia, Parissa.

In: Nature Genetics, 16.01.2017.

Research output: Contribution to journalArticle

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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.",
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AU - Via,Laura E.

AU - Cassell,Gail H.

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