The global phylogeography of rapidly expanding multidrug resistant Ural lineage 4.2 Mycobacterium tuberculosis

Abstract Multidrug resistant tuberculosis (MDR-TB) epidemics are sustained by transmission of reproductively fit MDR M. tuberculosis ( Mtb ) strains. We search a large publicly available dataset of ~200,000 Mtb whole genome sequences to identify strains related to a highly successful MDR clade circulating in Moldova belonging to lineage 4.2.1/Ural. We characterize a clade of 1604 drug-resistant Mtb sequences harboring conserved resistance-conferring mutations. We identify the Russian Federation as the most likely country of origin for this clade and infer several independent migration events from Russia and Moldova to other European and Asian countries. We estimate that this clade is expanding more rapidly than comparable clades of lineage 4.2.1/Ural. The broad dispersal of this highly successful clade is an urgent global health threat. Genomic surveillance is essential to track the evolution and spread of this and other strains of concern.