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.
Bibliographical noteFunding Information:
We thank: I Razio, P Vock, T Ubben and J Zallet from Borstel, Germany for technical assistance; the national and expatriate staff of Médecins Sans Frontières, Karakalpakstan; Dr. Atadjan and Dr. K Khamraev from the Ministry of Health (Karakalpakstan) for their support. Parts of this work have been supported by the European Union TB-PAN-NET (FP7-223681) project and the German Center for Infection Research and by the Leibniz Science Campus Evolutionary Medicine of the Lung (Evo-Lung). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Raw sequence data (fastq files) have been deposited at the European Nucleotide Archive (ENA) under the project number ERP000192.
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