High clustering rate and genotypic drug-susceptibility screening for the newly recommended anti-tuberculosis drugs among global extensively drug-resistant <i>Mycobacterium tuberculosis</i> isolates

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) make TB difficult to control. Global susceptibility data for six newly recommended anti-TB drugs against M/XDR-TB are still limited. Using publicly available whole-genome sequences, we determined the proportion of 513 phenotypically XDR-TB isolates that carried mutations associated with resistance against these drugs (bedaquiline, clofazimine, linezolid, delamanid, pretomanid and cycloserine). Mutations of <i>Rv0678</i> and <i>Rv1979c</i> were detected in 69/513 isolates (13.5%) for bedaquiline resistance and 79/513 isolates (15.4%) for clofazimine resistance with additional <i>mmpL5</i> mutations. Mutations conferring resistance to delamanid were detected in <i>fbiB</i> and <i>ddn</i> genes for 11/513 isolates (2.1%). For pretomanid, a mutation was detected in the <i>ddn</i> gene for 3/513 isolates (0.6%). Nineteen mutations of <i>pykA, cycA, ald</i>, and <i>alr</i> genes, conferring resistance to cycloserine, were found in 153/513 isolates (29.8%). No known mutations associated with linezolid resistance were detected. Cluster analysis showed that 408/513 isolates fell within 99 clusters and that 354 of these isolates were possible primary drug-resistant TB (292 XDR-TB, 57 pre-XDR-TB and 5 MDR-TB). Clonal transmission of primary XDR isolates might contribute significantly to the high prevalence of DR-TB globally.