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Nat Genet. 2014 Mar;46(3):279-86. doi: 10.1038/ng.2878. Epub 2014 Jan 26.

Evolution and transmission of drug-resistant tuberculosis in a Russian population.

Author information

1
Public Health England (PHE) National Mycobacterium Reference Laboratory, Clinical TB and HIV Group, Blizard Institute, Queen Mary University of London, London, UK.
2
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
3
Samara Oblast Tuberculosis Dispensary, Samara, Russian Federation.
4
Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
5
Department of Medicine, University of Cambridge, Cambridge, UK.
6
Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
7
1] Public Health England (PHE) National Mycobacterium Reference Laboratory, Clinical TB and HIV Group, Blizard Institute, Queen Mary University of London, London, UK. [2] Department of Infectious Diseases, Imperial College, London, UK.

Abstract

The molecular mechanisms determining the transmissibility and prevalence of drug-resistant tuberculosis in a population were investigated through whole-genome sequencing of 1,000 prospectively obtained patient isolates from Russia. Two-thirds belonged to the Beijing lineage, which was dominated by two homogeneous clades. Multidrug-resistant (MDR) genotypes were found in 48% of isolates overall and in 87% of the major clades. The most common rpoB mutation was associated with fitness-compensatory mutations in rpoA or rpoC, and a new intragenic compensatory substitution was identified. The proportion of MDR cases with extensively drug-resistant (XDR) tuberculosis was 16% overall, with 65% of MDR isolates harboring eis mutations, selected by kanamycin therapy, which may drive the expansion of strains with enhanced virulence. The combination of drug resistance and compensatory mutations displayed by the major clades confers clinical resistance without compromising fitness and transmissibility, showing that, in addition to weaknesses in the tuberculosis control program, biological factors drive the persistence and spread of MDR and XDR tuberculosis in Russia and beyond.

PMID:
24464101
PMCID:
PMC3939361
DOI:
10.1038/ng.2878
[Indexed for MEDLINE]
Free PMC Article

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