Compensatory evolution drives multidrug-resistant tuberculosis in Central Asia

Area of Science:

• Microbiology
• Genetics
• Epidemiology

Background:

• The drivers of the multidrug-resistant tuberculosis (MDR-TB) epidemic in the former Soviet Union are not fully understood.
• Understanding the evolutionary history and transmission of MDR-TB strains is crucial for effective control.

Purpose of the Study:

• To investigate the evolutionary history, emergence of resistance, and transmission networks of MDR-TB isolates in Karakalpakstan, Uzbekistan.
• To identify bacterial factors contributing to the MDR-TB epidemic in the region.

Main Methods:

• Whole genome sequencing of *Mycobacterium tuberculosis* complex isolates.
• Bayesian statistical analysis to determine evolutionary history and emergence of resistance.
• Analysis of transmission networks and fitness-associated mutations.

Main Results:

• A distinct clade, the Central Asian outbreak (CAO), emerged around 1974 and acquired resistance to eight anti-TB drugs.
• CAO strains, comprising 75% of MDR-TB isolates in 2005/2006, likely selected by standardized treatment introduced in 1998.
• Fitness-compensating mutations were associated with increased transmission success and drug resistance.
• CAO strains were also found in a Russian cohort, indicating wider dissemination.

Conclusions:

• The genetic makeup of the CAO strain poses a significant threat to current and new MDR-TB treatment regimens.
• Bacterial evolution and treatment selection have driven the MDR-TB epidemic in this region.
• Urgent strategies are needed to combat the spread of highly resistant TB strains.