Compensatory evolution drives multidrug-resistant tuberculosis in Central Asia

Elife. 2018 Oct 30;7:e38200. doi: 10.7554/eLife.38200.


Bacterial factors favoring the unprecedented multidrug-resistant tuberculosis (MDR-TB) epidemic in the former Soviet Union remain unclear. We utilized whole genome sequencing and Bayesian statistics to analyze the evolutionary history, temporal emergence of resistance and transmission networks of MDR Mycobacterium tuberculosis complex isolates from Karakalpakstan, Uzbekistan (2001-2006). One clade (termed Central Asian outbreak, CAO) dating back to 1974 (95% HPD 1969-1982) subsequently acquired resistance mediating mutations to eight anti-TB drugs. Introduction of standardized WHO-endorsed directly observed treatment, short-course in Karakalpakstan in 1998 likely selected for CAO-strains, comprising 75% of sampled MDR-TB isolates in 2005/2006. CAO-isolates were also identified in a published cohort from Russia (2008-2010). Similarly, the presence of mutations supposed to compensate bacterial fitness deficits was associated with transmission success and higher drug resistance rates. The genetic make-up of these MDR-strains threatens the success of both empirical and standardized MDR-TB therapies, including the newly WHO-endorsed short MDR-TB regimen in Uzbekistan.

Keywords: M. tuberculosis; MDR-TB; compensatory evolution; drug resistance; evolutionary biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / pharmacology
  • Disease Transmission, Infectious*
  • Drug Resistance, Multiple, Bacterial
  • Evolution, Molecular*
  • Humans
  • Molecular Epidemiology
  • Mutation
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / isolation & purification
  • Selection, Genetic
  • Tuberculosis, Multidrug-Resistant / epidemiology*
  • Tuberculosis, Multidrug-Resistant / microbiology*
  • Uzbekistan / epidemiology
  • Whole Genome Sequencing


  • Antitubercular Agents

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.