Genomic evidence supporting the clonal expansion of extensively drug-resistant tuberculosis bacteria belonging to a rare proto<b>-</b>Beijing genotype

Tuberculosis disease (TB), caused by <i>Mycobacterium tuberculosis</i>, is a major public health issue in Thailand. The high prevalence of modern Beijing (Lineage 2.2.1) strains has been associated with multi- and extensively drug-resistant infections (MDR-, XDR-TB), complicating disease control. The impact of rarer proto-Beijing (L2.1) strains is less clear. In our study of thirty-seven L2.1 clinical isolates spanning thirteen years, we found a high prevalence of XDR-TB cases (32.4%). With ≤ 12 pairwise SNP distances, 43.2% of L2.1 patients belong to MDR-TB or XDR-TB transmission clusters suggesting a high level of clonal expansion across four Thai provinces. All XDR-TB (100%) were likely due to transmission rather than inadequate treatment. We found a 47 mutation signature and a partial deletion of the <i>fadD14</i> gene in the circulating XDR-TB cluster, which can be used for surveillance of this rare and resilient <i>M. tuberculosis</i> strain-type that is causing increasing health burden. We also detected three novel deletion positions, a deletion of 1285 bp within <i>desA3</i> (Rv3230c)<i>,</i> large deletions in the <i>plcB, plcA,</i> and <i>ppe38</i> gene which may play a role in the virulence, pathogenesis or evolution of the L2.1 strain-type.