Evolution and transmission of drug-resistant tuberculosis in a Russian population.
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.
Public Health England (PHE) National Mycobacterium Reference Laboratory, Clinical TB and HIV Group, Blizard Institute, Queen Mary University of London, London, UK.
Nicola
N
Casali
Public Health England (PHE) National Mycobacterium Reference Laboratory, Clinical TB and HIV Group, Blizard Institute, Queen Mary University of London, London, UK.
Vladyslav
V
Nikolayevskyy
Public Health England (PHE) National Mycobacterium Reference Laboratory, Clinical TB and HIV Group, Blizard Institute, Queen Mary University of London, London, UK.
Yanina
Y
Balabanova
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Simon R
0000000315126194
SR
Harris
Samara Oblast Tuberculosis Dispensary, Samara, Russian Federation.
Olga
O
Ignatyeva
Samara Oblast Tuberculosis Dispensary, Samara, Russian Federation.
Irina
I
Kontsevaya
Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
Jukka
J
Corander
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Josephine
J
Bryant
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Julian
0000000270695958
J
Parkhill
Department of Medicine, University of Cambridge, Cambridge, UK.
Sergey
S
Nejentsev
Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Rolf D
RD
Horstmann
Public Health England (PHE) National Mycobacterium Reference Laboratory, Clinical TB and HIV Group, Blizard Institute, Queen Mary University of London, London, UK.
Timothy
T
Brown
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.
Francis
F
Drobniewski
D001426:Bacterial Proteins / Q000235:genetics; D012321:DNA-Directed RNA Polymerases; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D019143:Evolution, Molecular; D054908:Extensively Drug-Resistant Tuberculosis / Q000453:epidemiology / Q000382:microbiology / Q000635:transmission; D005798:Genes, Bacterial; D006801:Humans; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics* / Q000472:pathogenicity; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011446:Prospective Studies; D012426:Russia / Q000453:epidemiology; D018088:Tuberculosis, Multidrug-Resistant / Q000453:epidemiology / Q000382:microbiology / Q000635:transmission*; D014774:Virulence / Q000235:genetics
D001426:Bacterial Proteins; C505805:rpoB protein, Mycobacterium tuberculosis; D012321:DNA-Directed RNA Polymerases