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The ECDC0002 cluster, characterized by an unique 24-locus VNTR typing profile with a Beijing genotype signature, continues to spread in the European region and is responsible for a significant proportion of all clustered multidrug resistant tuberculosis (MDR-TB) cases in Eastern Europe. This prompted research on potential selective advantages in these strains. In 58 of 59 (98%) ECDC0002 cluster MDR-TB isolates tested, identical mutations (rpoB-S531L and katG-S315T) conferring rifampicin- and isoniazid resistance were detected. Whole genome sequencing of nine ECDC0002 isolates identified an unique rpoC-F452S mutation with a potential compensatory function for the expected loss of fitness due to the mutation in the rpoB gene. We screened for this mutation in other isolates with the ECDC0002 VNTR pattern, being MDR/XDR (n=24), INH-mono resistant (n=15) and pan-susceptible (n=2), from six different countries. In this set and also in an additional collection of strains (n=95) of different genotypes, susceptibility profiles and cluster sizes we found that the rpoC-F452S mutation was restricted to the MDR-TB isolates of the ECDC0002 cluster, suggesting this may be a crucial factor in the emergence of this MDR-TB cluster. Additionally, the rpoC-F452S mutation was only detected in isolates of the large European outbreak cluster with both a MDR phenotype and an embB-M306V mutation associated with ethambutol resistance. The rpoC-F452 mutation is potentially compensatory because of its appearance strictly in TB strains carrying a rpoB-S531L mutation and its location in the region usually harboring these compensatory mutations; it has arisen independently as an rpoC-F452C mutation in a non-Beijing genotype strain. The combination of the low-fitness-cost rpoB-S531L and katG-S315T mutations associated with rifampicin and isoniazid resistance and the putative compensatory rpoC-F452S mutation may, in part, explain the successful spread of this MDR-TB outbreak strain. This “super-spreader” strain demands continued monitoring and fundamental research is required into its evolutionary development, as the spread of highly transmissible MDR strains threatens TB control efforts worldwide. |