Compensatory evolution drives multidrug-resistant tuberculosis in Central Asia

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-MTBC strains from Karakalpakstan, Uzbekistan (2001-2006). One MTBC-clone (termed Central Asian outbreak, CAO) with resistance mediating mutations to eight anti-TB drugs existed prior the worldwide introduction of standardized WHO-endorsed directly observed treatment, short-course (DOTS). DOTS implementation in Karakalpakstan in 1998 likely selected for these CAO-strains, comprising 75% of sampled MDR-TB strains in 2005/2006. CAO-strains were also identified in a previously published cohort from Samara, Russia (2008-2010). Similarly, transmission success and resistance development was linked to mutations compensating fitness deficits associated with rifampicin resistance. The genetic make-up of these outbreak clades threatens the success of both empirical and standardized guideline driven MDR-TB therapies, including the newly WHO-endorsed short MDR-TB regimen in Uzbekistan.