Evolution and emergence of multidrug-resistant mycobacterium tuberculosis in chisinau, moldova

Tyler S. Brown, Vegard Eldholm, Ola Brynildsrud, Magnus Osnes, Natalie Levy, James Stimson, Caroline Colijn, Sofia Alexandru, Ecaterina Noroc, Nelly Ciobanu, Valeriu Crudu, Ted Cohen, Barun Mathema*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The evolution and emergence of drug-resistant tuberculosis (TB) has been studied extensively in some contexts, but the ecological drivers of these two processes remain poorly understood. This study sought to describe the joint evolutionary and epidemiological histories of a novel multidrug-resistant Mycobacterium tuberculosis strain recently identified in the capital city of the Republic of Moldova (MDR Ural/4.2), where genomic surveillance of drug-resistant M. tuberculosis has been limited thus far. Using whole genome sequence data and Bayesian phylogenomic methods, we reconstruct the stepwise acquisition of drug resistance mutations in the MDR Ural/4.2 strain, estimate its historical bacterial population size over time, and infer the migration history of this strain between Eastern European countries. We infer that MDR Ural/4.2 likely evolved (via acquisition of rpoB S450L, which confers resistance to rifampin) in the early 1990s, during a period of social turmoil following Moldovan independence from the Soviet Union. This strain subsequently underwent substantial population size expansion in the early 2000s, at a time when national guidelines encouraged inpatient treatment of TB patients. We infer exportation of this strain and its isoniazid-resistant ancestral precursor from Moldova to neighbouring countries starting as early as 1985. Our findings suggest temporal and ecological associations between specific public health practices, including inpatient hospitalization of drug-resistant TB cases from the early 2000s until 2013, and the evolution of drug-resistant M. tuberculosis in Moldova. These findings underscore the need for regional coordination in TB control and expanded genomic surveillance efforts across Eastern Europe.

Original languageEnglish
Article number000620
JournalMicrobial Genomics
Issue number8
Publication statusPublished - 2021

Bibliographical note

Funding Information:
This study was funded by the United States National Institutes of Health (NIH T32AI007061 to TSB), the International Union Against Tuberculosis and Lung Disease, and the United States Agency for International Development. None of the funding bodies had any role in the design of the study or collection, analysis, and interpretation of data or in writing the manuscript.

Publisher Copyright:
© 2021 The Authors.


  • Antimicrobial resistance
  • Epidemiology
  • Mycobacterium tuberculosis
  • Outbreaks
  • Phylogenomics


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