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Nat Genet. 2017 Mar;49(3):395-402. doi: 10.1038/ng.3767. Epub 2017 Jan 16.

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

Author information

1
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2
KwaZulu-Natal Research Institute for TB and HIV (K-RITH), Durban, South Africa.
3
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4
Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands.
5
Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
6
National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
7
Medical Research Council, TB Platform, Pretoria, South Africa.
8
International Tuberculosis Research Center, Changwon and Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea.
9
Office of Cyber Infrastructure and Computational Biology, National Institutes of Health, Rockville, Maryland, USA.
10
Clinical Hospital of Pneumology Leon Daniello, Cluj Napoca, Romania.
11
Department of Medical Microbiology, Mycobacteriology Laboratory, Makerere University, Kampala, Uganda.
12
Public Health Agency of Sweden, Solna, Sweden.
13
University of Sciences, Techniques and Technologies of Bamako (USTTB), Bamako, Mali.
14
Novasano Health and Science, New York, New York, USA.
15
Microbiology and Morphology Laboratory, Phthisiopneumology Institute, Chisinau, Moldova.
16
Mycobacteriology Research Centre, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
17
Republican Research and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus.
18
Department of Global Health and Social Medicine, Harvard Medical School, Division of Global Health Equity, Brigham and Women's Hospital, Boston, Massachusetts, USA.
19
Section of Infectious Diseases, Boston Medical Center, Boston, Massachusetts, USA.
20
Department of Biomedical Engineering and Microbiology, Boston University, Boston, Massachusetts, USA.
21
National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
22
National Institute for Research in Tuberculosis, Chennai, India.
23
Rutgers-New Jersey Medical School, Newark, New Jersey, USA.
24
Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
25
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, USA.

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.

PMID:
28092681
PMCID:
PMC5402762
DOI:
10.1038/ng.3767
[Indexed for MEDLINE]
Free PMC Article
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