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Molecular evolutionary analysis of a clade of closely-related Delamanid-resistant Mycobacterium tuberculosis (M.tb) strains from Eastern Europe and Central Asia.

K R Wollenberg(1) M Harris(1) A Gabrielian(1) N Ciobanu(2) V Crudu(2) N Shubladze(3) A Rosenthal(1)

1:National Institute of Allergy and Infectious Diseases; 2:Institute of Phthisiopneumology; 3:National Center for Tuberculosis and Lung Diseases of Georgia

Drug-resistant (DR) tuberculosis is a global health issue. Highly resistant cases require the development of novel antibiotics, such as Delamanid. To study molecular mechanisms of developing drug resistance, NIAID TB Portals Program had sequenced and analyzed more than 3300 genomes of M. tuberculosis. Among these, we identified a phylogenetically robust clade of Lineage 2 samples with the Delamanid resistance variant ddn Trp88Stop. Twelve of these samples were from Georgia, five were from Moldova, and one each were from Ukraine and Azerbaijan. The literature provided six additional samples from Tajikistan and eight from Moldova with this DR variant. These samples clustered within the previously-identified clade of TB Portals database Lineage 2 samples. Additional analysis of sample dates and sequence diversity indicated potential transmission clusters within this clade. Two additional samples from Georgia and three from Moldova were from lineage 4 and had this Delamanid resistance mutation. Among all samples some relationships were consistent with the spreading of a specific Delamanid-resistant strain of M.tb across international borders in this region. Other samples in this analysis could be the result of parallel acquisition of delamanid resistance in co-circulating, closely related clones. The distribution of the ddn Trp88Stop mutation across taxonomic lineages demonstrates independent acquisition of novel drug resistance. We demonstrated that Delamanid resistance is spreading through central Asia and eastern Europe by a combination of the transmission of resistant clones and the rapid acquisition of a specific drug-resistance mutation, further supporting the need for adherence to WHO recommendations for DR-TB treatment.

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