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

The molecular mechanisms determining 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. MDR genotypes were found in 48% of isolates overall and 87% of the major clades. The most common rifampicin-resistance rpoB mutation was associated with fitness-compensatory mutations in rpoA or rpoC, and a novel intragenic compensatory substitution was identified. The proportion of MDR cases with 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 confer clinical resistance without compromising fitness and transmissibility, revealing a biological contribution to the tuberculosis program weaknesses driving the persistence and spread of M/XDR-tuberculosis in Russia and beyond.